The Experts below are selected from a list of 21939 Experts worldwide ranked by ideXlab platform
Paul M. Harari - One of the best experts on this subject based on the ideXlab platform.
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Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR Inhibitors and radiation
Cancer research, 2012Co-Authors: Shyhmin Huang, Eric A. Armstrong, Chimera R. Peet, Jarob Saker, Lukas C. Amler, Mark X. Sliwkowski, Paul M. HarariAbstract:EGF receptor (EGFR) inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR Inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR Inhibitors, could inhibit tumor growth and cell-cycle progression in parallel with EGFR/HER3 signaling pathway modulation. MEHD7945A was more effective than a combination of cetuximab and anti-HER3 antibody at inhibiting both EGFR/HER3 signaling and tumor growth. In human tumor xenograft models, we confirmed the greater antitumor potency of MEHD7945A than cetuximab or erlotinib. MEHD7945A retained potent activity in tumors refractory to EGFR inhibitor alone. Furthermore, MEHD7945A also limited cross-resistance to radiation in EGFR inhibitor–resistant cells by modulating cell-cycle progression and repair processes that control apoptotic cell death. Taken together, our findings confirm an important role of compensatory HER3 signaling in the development of acquired resistance to EGFR Inhibitors and offer preclinical proof-of-concept that MEHD7945A can effectively overcome EGFR inhibitor resistance. Cancer Res; 73(2); 824–33. ©2012 AACR .
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p53 Modulates Acquired Resistance to EGFR Inhibitors and Radiation
Cancer research, 2011Co-Authors: Shyhmin Huang, S. Benavente, Eric A. Armstrong, Deric L. Wheeler, Paul M. HarariAbstract:There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) Inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor-resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR Inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR Inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor-resistant cells was sufficient to resensitize them to EGFR Inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR Inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR Inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR Inhibitors and radiation.
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Abstract 637: MEHD7945A, an EGFR/ErbB3 dual specific antibody, overcomes acquired resistance to EGFR Inhibitors in head and neck and lung tumors
Experimental and Molecular Therapeutics, 2011Co-Authors: Shyhmin Huang, Mark X. Sliwkowski, Paul M. HarariAbstract:The development of acquired resistance to EGFR Inhibitors is emerging as a potential treatment barrier for EGFR targeted therapies. Efforts to better understand underlying mechanisms of acquired resistance to EGFR Inhibitors, and strategies to overcome this resistance are highly desired. We have previously identified that acquired resistance to EGFR Inhibitors may result from the trans-activation of ErbB3 by EGFR. We therefore examined the capacity of the EGFR/ErbB3 dual specific antibody, MEHD7945A to overcome acquired resistance to EGFR Inhibitors. We first examined the antiproliferative effects of MEHD7945A across a panel of human head and neck (HNSCC) and non-small cell lung (NSCLC) tumor cell lines. MEHD7945A significantly inhibited the proliferation in tumors cells that express EGFR and ErbB3. We then applied MEHD7945A to EGFR inhibitor-resistant clones from HNSCC (SCC-1 and SCC-6) and NSCLC lines (H226) that have been chronically exposed to cetuximab or erlotinib and show EGFR inhibitor-resistant phenotypes. Using identical doses of MEHD7945A and cetuximab, we found that MEHD7945A inhibited the growth of tumor cells that exhibit resistance to cetuximab. Similar results were observed in our erlotinib-resistant clones. MEHD7945A also significantly inhibited EGFR and ErbB3-dependent downstream signaling. Additional studies to confirm the antitumor activity of MEHD7945A in xenograft models using EGFR inhibitor-resistant clones are in progress. In addition, studies to investigate the impact of MEHD7945A on radiation response profiles in a panel of HNSCC, NSCLC and EGFR-inhibitor resistant cell lines are underway. These data not only support an important role of ErbB3 in acquired resistance to EGFR Inhibitors but also suggest MEHD7945A may provide a valuable treatment strategy for patients who develop acquired resistance to EGFR targeting agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 637. doi:10.1158/1538-7445.AM2011-637
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understanding resistance to EGFR Inhibitors impact on future treatment strategies
Nature Reviews Clinical Oncology, 2010Co-Authors: Deric L. Wheeler, Emily F Dunn, Paul M. HarariAbstract:EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular Inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR, preclinical and clinical development of EGFR Inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of Inhibitors for the treatment of cancer.
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Clinical application of EGFR Inhibitors in head and neck squamous cell cancer.
Cancer Treatment and Research, 2008Co-Authors: Igor Astsaturov, Roger B. Cohen, Paul M. HarariAbstract:Epidermal growth factor receptor (EGFR) signaling inhibition represents a highly promising arena for the application of molecularly targeted cancer therapies. Evolving from several decades of systematic research in cancer cell biology, a series of EGFR Inhibitors from both the monoclonal antibody (mAb) and tyrosine kinase inhibitor (TKI) class have been developed and entered the clinic. Four EGFR Inhibitors have recently gained FDA approval for cancer therapy in the United States (and many other countries) including the mAbs cetuximab (Erbitux) and panitumumab (Vectibix), and the small molecule TKIs gefitinib (Iressa) and erlotinib (Tarceva). The rapidly expanding preclinical and clinical data supporting the FDA drug registrations validate a central role for the EGFR as an important molecular target in epithelial malignancies. In this report, we highlight the relevant aspects of EGFR biology and the translation of these observations into recent treatment advances in head and neck squamous cell cancer (HNSCC). Key recent clinical findings include a survival advantage for the addition of the anti-EGFR monoclonal antibody cetuximab to definitive radiation therapy in patients with locoregionally advanced HNSCC, and palliative benefits for the use of cetuximab in patients with incurable HNSCC. Small molecule EGFR TKIs also show considerable promise in this disease, alone and in combination with radiation and chemotherapy. Both classes of anti-EGFR agent are generally well-tolerated with side effects (notably skin rash) that are distinct from those of conventional chemotherapy. Recently completed and ongoing clinical trials will continue to refine the role for EGFR Inhibitors in all treatment phases of HNSCC [1, 2]. Concurrent chemoradiation has emerged worldwide as a standard of care for many patients with locoregionally advanced HNSCC [3]. With state-of-the-art radiation (RT) and chemotherapy (along with nodal dissection and salvage surgery, when appropriate) multidisciplinary teams regularly achieve cure rates of approximately 40–50% for stage III and 30% for stage IV HNSCC patients [4] with recently published studies showing even better disease-free and overall 7 Clinical Application of EGFR Inhibitors in Head and Neck Squamous Cell Cancer
Pasi A Janne - One of the best experts on this subject based on the ideXlab platform.
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EGFR mutated lung cancers resistant to osimertinib through EGFR c797s respond to first generation reversible EGFR Inhibitors but eventually acquire EGFR t790m c797s in preclinical models and clinical samples
Journal of Thoracic Oncology, 2019Co-Authors: Deepa Rangachari, Pasi A Janne, Mierzhati Mushajiang, Jason E Shpilsky, Paul A Vanderlaan, Susumu Kobayashi, Christie J Lau, Cloud P Paweletz, Geoffrey R Oxnard, Daniel B CostaAbstract:Abstract Introduction Osimertinib is approved for advanced EGFR-mutated NSCLC, and identification of on-target mechanisms of resistance (i.e., EGFR C797S) to this third-generation EGFR inhibitor are evolving. Whether durable control of subsequently osimertinib-resistant NSCLC with the EGFR-sensitizing mutation (SM)/C797S is possible with first-generation EGFR Inhibitors (such as gefitinib or erlotinib) remains underreported, as does the resultant acquired resistance profile. Methods We used N-ethyl-N-nitrosourea mutagenesis to determine the profile of EGFR SM/C797S preclinical models exposed to reversible EGFR Inhibitors. In addition, we retrospectively probed a case of EGFR SM lung adenocarcinoma treated with first-line osimertinib, followed by second-line erlotinib in the setting of EGFR SM/C797S. Results Use of N-ethyl-N-nitrosourea mutagenesis against the background of EGFR L858R/C797S in conjunction with administration of gefitinib revealed preferential outgrowth of cells with EGFR L858R/T790M/C797S. A patient with EGFR delE746_T751insV NSCLC was treated with osimertinib with sustained response for 10 months before acquiring EGFR C797S. The patient was subsequently treated with erlotinib, with response for a period of 4 months, but disease progression ensued. Liquid biopsy disclosed EGFR delE746_T751insV with T790M and C797S present in cis. Conclusion EGFR SM NSCLC can acquire resistance to osimertinib through development of the EGFR C797S mutation. In this clinical scenario, the tumor may respond transiently to reversible first-generation EGFR Inhibitors (gefitinib or erlotinib), but evolving mechanisms of on-target resistance—in clinical specimens and preclinical systems—indicate that EGFR C797S along with EGFR T790M can evolve. This report adds to the growing understanding of tumor evolution or adaptability to sequential EGFR inhibition and augments support for exploring combination therapies to delay or prevent on-target resistance.
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toward discovery of mutant EGFR Inhibitors design synthesis and in vitro biological evaluation of potent 4 arylamino 6 ureido and thioureido quinazoline derivatives
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Pasi A Janne, Samar Mowafy, A Galanis, Zainab M Doctor, Raymond M Paranal, Deena S Lasheen, Nahla A Farag, Khaled A M AbouzidAbstract:Abstract A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR Inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC 50 values in the low nanomolar range ( 4d , 6f , 7e showed significant inhibition (IC 50 = 1.76–2.38 μM) in these mutant lines and significant Her2 enzyme inhibition (IC 50 = 19.2–40.6 nM) compared to lapatinib (60.1 nM). The Binding mode of compounds 6d , 6f , 7a , 7b and 8b were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds 6f and 7e showed about eight and three folds respectively greater potency than gefitinib. Our structure–activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing Inhibitors against wild type and mutant EGFR.
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toward discovery of mutant EGFR Inhibitors design synthesis and in vitro biological evaluation of potent 4 arylamino 6 ureido and thioureido quinazoline derivatives
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Pasi A Janne, Samar Mowafy, A Galanis, Zainab M Doctor, Raymond M Paranal, Deena S Lasheen, Nahla A Farag, Khaled A M AbouzidAbstract:A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR Inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50 values in the low nanomolar range (<0.495-9.05nM) and displayed more potent cytotoxic effect in BaF/3 expressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3 expressing Del19/T790M and Ba/F3 expressing L858R/T790M were assayed. Compounds 4d, 6f, 7e showed significant inhibition (IC50=1.76-2.38μM) in these mutant lines and significant Her2 enzyme inhibition (IC50=19.2-40.6nM) compared to lapatinib (60.1nM). The Binding mode of compounds 6d, 6f, 7a, 7b and 8b were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds 6f and 7e showed about eight and three folds respectively greater potency than gefitinib. Our structure-activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing Inhibitors against wild type and mutant EGFR.
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Abstract IA31: Mechanisms of resistance to EGFR Inhibitors in lung cancer
Mechanisms of Resistance, 2016Co-Authors: Pasi A JanneAbstract:Epidermal Growth Factor Receptor (EGFR) tyrosine kinase Inhibitors (TKIs), including geftinib, erlotinib and afatinib are the standard of care for patients with advanced EGFR mutant non-small cell lung cancer. Treatment with an EGFR TKI leads to a response rate of ~60% and a median progression free survival ranging from 9 to 11 months. Acquired drug resistance inevitably develops in most of not all EGFR mutant lung cancer patients treated with EGFR Inhibitors. The most common mechanism of acquired resistance is the development of a secondary EGFR T790M mutation. Other mechanism of resistance include activation of bypass signaling pathways (such as MET or HER2) and histological transformation. Over the last few years a series of new structurally distinct EGFR Inhibitors have been identified and entered the clinic that are capable of inhibiting EGFR T790M. This class of mutant selective EGFR TKIs are effective both against the activating EGFR mutation and the drug resistant T790M but spare inhibition of wild type (WT) EGFR. This has enormous potential therapeutic implications as the side effects of all approved EGFR Inhibitors is derived from inhibition of WT EGFR. Several of these agents, including AZD9291 and rociletinib (CO-1686) are in advanced stage clinical development. Both agents have been granted FDA’s breakthrough designation. In EGFR inhibitor resistant patients who have developed resistance to current clinical EGFR Inhibitors through T790M, the response rates to either AZD9291 or rociletinib is over 60% with median progression free survivals of ~ 10 months. Current research efforts and clinical studies are focusing on a.) understanding mechanisms of drug resistance to this new class of EGFR Inhibitors, b.) the development of rationale combination therapies and c.) use of these agents as initial treatment (instead of currently approved EGFR Inhibitors) for patients with advanced EGFR mutant NSCLC. Citation Format: Pasi Janne. Mechanisms of resistance to EGFR Inhibitors in lung cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA31.
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EGFR mutations and resistance to irreversible pyrimidine based EGFR Inhibitors
Clinical Cancer Research, 2015Co-Authors: Dalia Ercan, Nathanael S. Gray, Hwan Geun Choi, Caihong Yun, Marzia Capelletti, Ting Xie, Michael J Eck, Pasi A JanneAbstract:Purpose: Mutant selective irreversible pyrimidine-based EGFR kinase Inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR Inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents. Experimental Design: We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR -mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug-resistant clones. We evaluated the sensitivity of EGFR Inhibitors in models harboring drug-resistant EGFR mutations. Results: We identified 3 major drug resistance mutations. EGFR L718Q, L844V, and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance. Cells containing an EGFR -sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V, or C797S retain sensitivity to quinazoline-based EGFR Inhibitors, gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR Inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization. Conclusions: Our findings provide insights into resistance mechanisms to irreversible pyrimidine-based EGFR Inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR Inhibitors. These findings will guide the development of new strategies to inhibit EGFR. Clin Cancer Res; 21(17); 3913–23. ©2015 AACR . See related commentary by Ayeni et al., p. 3818
Lecia V. Sequist - One of the best experts on this subject based on the ideXlab platform.
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role of epidermal growth factor receptor EGFR Inhibitors and radiation in the management of brain metastases from EGFR mutant lung cancers
Oncologist, 2018Co-Authors: Melin Khandekar, Zofia Piotrowska, Henning Willers, Lecia V. SequistAbstract:: The growth of genotype-directed targeted therapies, such as Inhibitors of the epidermal growth factor receptor (EGFR), has revolutionized treatment for some patients with oncogene-addicted lung cancer. However, as systemic control for these patients has improved, brain metastases remain an important source of morbidity and mortality. Traditional treatment for brain metastases has been radiotherapy, either whole-brain radiation or stereotactic radiosurgery. The growing availability of drugs that can cross the blood-brain barrier and have activity in the central nervous system (CNS) has led to many studies investigating whether targeted therapy can be used in combination with or in lieu of radiation. In this review, we summarize the key literature about the incidence and nature of EGFR-mutant brain metastases (EGFR BMs), the data about the activity of EGFR Inhibitors in the CNS, and whether they can be used as front-line therapy for brain metastases. Although initial use of tyrosine kinase Inhibitors for EGFR BMs can often be an effective treatment strategy, multidisciplinary evaluation is critical, and prospective studies are needed to clarify which patients may benefit from early radiotherapy. IMPLICATIONS FOR PRACTICE: Management of brain metastases in epidermal growth factor receptor (EGFR) mutant lung cancer is a common clinical problem. The question of whether to start initial therapy with an EGFR inhibitor or radiotherapy (either whole-brain radiotherapy or stereotactic radiosurgery) is controversial. The development of novel EGFR Inhibitors with enhanced central nervous system (CNS) penetration is an important advance in the treatment of CNS disease. Multidisciplinary evaluation and evaluation of extracranial disease status are critical to choosing the best treatment option for each patient.
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the allelic context of the c797s mutation acquired upon treatment with third generation EGFR Inhibitors impacts sensitivity to subsequent treatment strategies
Clinical Cancer Research, 2015Co-Authors: Matthew J Niederst, Lecia V. Sequist, Hillary Mulvey, Elizabeth L Lockerman, A Garcia, Zofia Piotrowska, Jeffrey A EngelmanAbstract:Purpose A secondary EGFR mutation, T790M, is the most common resistance mechanism in EGFR-mutant adenocarcinomas that have progressed on erlotinib. Third-generation EGFR Inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients. However, acquired resistance mechanisms in patients treated with these drugs are yet to be described. Experimental design To study acquired resistance to third-generation EGFR Inhibitors, T790M-positive cells derived from an erlotinib-resistant cancer were made resistant to a third-generation TKI and then characterized using cell and molecular analyses. Results Cells resistant to a third-generation TKI acquired an additional EGFR mutation, C797S, which prevented suppression of EGFR. Our results demonstrate that the allelic context in which C797S was acquired may predict responsiveness to alternative treatments. If the C797S and T790M mutations are in trans, cells will be resistant to third-generation EGFR TKIs, but will be sensitive to a combination of first- and third-generation TKIs. If the mutations are in cis, no EGFR TKIs alone or in combination can suppress activity. If C797S develops in cells wild-type for T790 (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs. Conclusions Mutation of C797S in EGFR is a novel mechanism of acquired resistance to third-generation TKIs. The context in which the C797S develops with respect to the other EGFR alleles affects the efficacy of subsequent treatments.
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abstract 955 transformation from nsclc to sclc in EGFR mutant lung cancers with acquired resistance to EGFR Inhibitors
Cancer Research, 2014Co-Authors: Matthew J Niederst, Lecia V. Sequist, Elizabeth L Lockerman, A Garcia, Gad Getz, Carlotta Costa, Farhiya Mohamoud, Darrell R Borger, Toshi Shioda, A J IafrateAbstract:Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs) are sensitive to the EGFR Inhibitors erlotinib and gefitinib. In the majority of patients with this type of cancer, EFGR inhibition leads to a dramatic reduction in tumor size coupled with an abatement of symptoms. These responses are temporary, and in most cases the cancers become resistant after an average of one year. Recently, we and others have found that a subset of these cancers transform from NSCLC to SCLC as they acquire resistance to EGFR TKI. Details underlying this novel resistance mechanism are largely undiscovered. To assess the genetic changes associated with NSCLC to SCLC transformation, we carried out next generation sequencing analysis on NSCLC and SCLC resistant tumors. The sequencing results revealed that Rb, along with p53 and PIK3CA were specifically altered in the SCLC transformed tumors. An IHC assay to detect Rb indicated that while 10 out of 10 SCLC transformed cases have loss of Rb, resistant cancers that maintained an NSCLC histology largely retained Rb. To address the mechanism underlying the resistance to EGFR inhibition in these tumors, we demonstrated that upon the transformation to SCLC there is a marked reduction in EGFR expression, suggesting that in transforming to SCLC these cells become a cell type that no longer requires EGFR for their survival. Finally, utilizing cell lines generated from biopsies taken from resistant cancers, we identify the Bcl-2/Bcl-XL inhibitor Abt-263 as a potential therapeutic approach to treat these resistant patients. Together, our results provide details underlying this novel mechanism of resistance to targeted therapy. Citation Format: Matthew J. Niederst, Lecia V. Sequist, Elizabeth L. Lockerman, Angel R. Garcia, Carlotta Costa, Farhiya Mohamoud, Darrell R. Borger, Toshi Shioda, Gad Getz, Anthony J. Iafrate, Mari Mino-Kenudson, Jeffrey A. Engelman. Transformation from NSCLC to SCLC in EGFR mutant lung cancers with acquired resistance to EGFR Inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 955. doi:10.1158/1538-7445.AM2014-955
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Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Science translational medicine, 2011Co-Authors: Lecia V. Sequist, Belinda A. Waltman, Dora Dias-santagata, Subba R. Digumarthy, Alexa B. Turke, Panos Fidias, Kristin Bergethon, Alice T. Shaw, Scott N. Gettinger, Arjola K. CosperAbstract:Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase Inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non–small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR Inhibitors. Collectively, these results deepen our understanding of resistance to EGFR Inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.
Nathanael S. Gray - One of the best experts on this subject based on the ideXlab platform.
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Abstract 4935: High-throughput immune-oncology screen identifies EGFR Inhibitors as potent enhancers of CTL antigen-specific tumor cell killing
Cancer Research, 2018Co-Authors: Patrick H. Lizotte, Mark A. Bittinger, Megan E. Cavanaugh, Luke J. Taus, Abha Dhaneshwar, Naomi Mayman, Aaron Yang, Troy A. Luster, Paul Kirschmeier, Nathanael S. GrayAbstract:As immune checkpoint blocking antibodies increasing become foundational therapies for the treatment of cancer, there is a pressing need to identify compounds that synergize with checkpoint blockade as the basis of combinatorial treatment regimens. We have developed a screening assay in which a luciferized tumor cell line expressing a model antigen is co-cultured with a transgenic CD8+ T cell specifically recognizing the model antigen in a H-2b-restricted manner. The target tumor cell/T cell assay was screened with a small molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells in an antigen-dependent manner. The EGFR inhibitor Erlotinib was the top hit that enhanced T cell killing of tumor cells. Subsequent experiments with Erlotinib and additional EGFR Inhibitors validated the screen result. EGFR Inhibitors increase both basal and IFN-γ-induced antigen processing and presentation of MHC class-I, which enhanced recognition and lysis by CD8+ cytotoxic T lymphocytes. The tumor cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen utilizing the same target tumor cell/T cell assay identified sgRNAs targeting EGFR as sensitizing tumor cells to T cell-mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in the MC38 syngeneic colon cancer model that was superior to PD-1 blockade or EGFR inhibition alone, further validating EGFR Inhibitors as immunomodulatory agents that enhance PD-1 checkpoint blockade. This novel target tumor cell/T cell assay can be screened in high-throughput with small molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds AND target genes, respectively, that enhance or inhibit T cell recognition and killing of tumor cells. Citation Format: Patrick H. Lizotte, Troy Luster, Megan E. Cavanaugh, Luke J. Taus, Abha Dhaneshwar, Naomi Mayman, Aaron Yang, Mark Bittinger, Paul Kirschmeier, Nathanael S. Gray, David A. Barbie, Pasi A. Janne. High-throughput immune-oncology screen identifies EGFR Inhibitors as potent enhancers of CTL antigen-specific tumor cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4935.
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EGFR mutations and resistance to irreversible pyrimidine based EGFR Inhibitors
Clinical Cancer Research, 2015Co-Authors: Dalia Ercan, Nathanael S. Gray, Hwan Geun Choi, Caihong Yun, Marzia Capelletti, Ting Xie, Michael J Eck, Pasi A JanneAbstract:Purpose: Mutant selective irreversible pyrimidine-based EGFR kinase Inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR Inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents. Experimental Design: We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR -mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug-resistant clones. We evaluated the sensitivity of EGFR Inhibitors in models harboring drug-resistant EGFR mutations. Results: We identified 3 major drug resistance mutations. EGFR L718Q, L844V, and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance. Cells containing an EGFR -sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V, or C797S retain sensitivity to quinazoline-based EGFR Inhibitors, gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR Inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization. Conclusions: Our findings provide insights into resistance mechanisms to irreversible pyrimidine-based EGFR Inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR Inhibitors. These findings will guide the development of new strategies to inhibit EGFR. Clin Cancer Res; 21(17); 3913–23. ©2015 AACR . See related commentary by Ayeni et al., p. 3818
Shyhmin Huang - One of the best experts on this subject based on the ideXlab platform.
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Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR Inhibitors and radiation
Cancer research, 2012Co-Authors: Shyhmin Huang, Eric A. Armstrong, Chimera R. Peet, Jarob Saker, Lukas C. Amler, Mark X. Sliwkowski, Paul M. HarariAbstract:EGF receptor (EGFR) inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR Inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR Inhibitors, could inhibit tumor growth and cell-cycle progression in parallel with EGFR/HER3 signaling pathway modulation. MEHD7945A was more effective than a combination of cetuximab and anti-HER3 antibody at inhibiting both EGFR/HER3 signaling and tumor growth. In human tumor xenograft models, we confirmed the greater antitumor potency of MEHD7945A than cetuximab or erlotinib. MEHD7945A retained potent activity in tumors refractory to EGFR inhibitor alone. Furthermore, MEHD7945A also limited cross-resistance to radiation in EGFR inhibitor–resistant cells by modulating cell-cycle progression and repair processes that control apoptotic cell death. Taken together, our findings confirm an important role of compensatory HER3 signaling in the development of acquired resistance to EGFR Inhibitors and offer preclinical proof-of-concept that MEHD7945A can effectively overcome EGFR inhibitor resistance. Cancer Res; 73(2); 824–33. ©2012 AACR .
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p53 Modulates Acquired Resistance to EGFR Inhibitors and Radiation
Cancer research, 2011Co-Authors: Shyhmin Huang, S. Benavente, Eric A. Armstrong, Deric L. Wheeler, Paul M. HarariAbstract:There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) Inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor-resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR Inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR Inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor-resistant cells was sufficient to resensitize them to EGFR Inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR Inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR Inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR Inhibitors and radiation.
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Abstract 637: MEHD7945A, an EGFR/ErbB3 dual specific antibody, overcomes acquired resistance to EGFR Inhibitors in head and neck and lung tumors
Experimental and Molecular Therapeutics, 2011Co-Authors: Shyhmin Huang, Mark X. Sliwkowski, Paul M. HarariAbstract:The development of acquired resistance to EGFR Inhibitors is emerging as a potential treatment barrier for EGFR targeted therapies. Efforts to better understand underlying mechanisms of acquired resistance to EGFR Inhibitors, and strategies to overcome this resistance are highly desired. We have previously identified that acquired resistance to EGFR Inhibitors may result from the trans-activation of ErbB3 by EGFR. We therefore examined the capacity of the EGFR/ErbB3 dual specific antibody, MEHD7945A to overcome acquired resistance to EGFR Inhibitors. We first examined the antiproliferative effects of MEHD7945A across a panel of human head and neck (HNSCC) and non-small cell lung (NSCLC) tumor cell lines. MEHD7945A significantly inhibited the proliferation in tumors cells that express EGFR and ErbB3. We then applied MEHD7945A to EGFR inhibitor-resistant clones from HNSCC (SCC-1 and SCC-6) and NSCLC lines (H226) that have been chronically exposed to cetuximab or erlotinib and show EGFR inhibitor-resistant phenotypes. Using identical doses of MEHD7945A and cetuximab, we found that MEHD7945A inhibited the growth of tumor cells that exhibit resistance to cetuximab. Similar results were observed in our erlotinib-resistant clones. MEHD7945A also significantly inhibited EGFR and ErbB3-dependent downstream signaling. Additional studies to confirm the antitumor activity of MEHD7945A in xenograft models using EGFR inhibitor-resistant clones are in progress. In addition, studies to investigate the impact of MEHD7945A on radiation response profiles in a panel of HNSCC, NSCLC and EGFR-inhibitor resistant cell lines are underway. These data not only support an important role of ErbB3 in acquired resistance to EGFR Inhibitors but also suggest MEHD7945A may provide a valuable treatment strategy for patients who develop acquired resistance to EGFR targeting agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 637. doi:10.1158/1538-7445.AM2011-637
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Combining EGFR Inhibitors with radiation or chemotherapy: will preclinical studies predict clinical results?
International journal of radiation oncology biology physics, 2004Co-Authors: Paul M. Harari, Shyhmin HuangAbstract:Abstract Purpose To highlight some of the preclinical data that examine the interaction of epidermal growth factor receptor (EGFR) Inhibitors with radiotherapy and chemotherapy. Methods and materials Recognition of the EGFR as an important regulator of tumor cell growth in the early 1980s stimulated the development of a series of molecules specifically designed to inhibit EGFR signaling as anticancer agents. Many of these agents have now matured and are in advanced clinical trial investigations, with tumor response rates on the order of 10–20% identified across a variety of human malignancies. Initially designed primarily as "cytostatic" agents, as opposed to "cytotoxic" agents, it is possible that the EGFR Inhibitors will realize their optimal clinical impact when delivered in concert with conventional cytotoxic modalities such as radiotherapy and/or chemotherapy. Results Despite very strong in vitro and in vivo preclinical results, several major gaps remain in our knowledge regarding the EGFR inhibitor mechanisms of interaction with radiotherapy and chemotherapy, with considerable selection bias in the publication of preclinical data available to date. Conclusion By acknowledging the limitations of the available preclinical data and by expanding our mechanistic understanding of EGFR inhibitor function in representative tumor model systems, we should enhance our capacity to predict the most rational and successful methods to combine EGFR Inhibitors with cytotoxic modalities in future clinical trials.