Cyclin-Dependent Kinase 4

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 297189 Experts worldwide ranked by ideXlab platform

Seth A Wander - One of the best experts on this subject based on the ideXlab platform.

  • abstract b23 genomic sequencing of metastatic hormone receptor positive breast cancer implicates akt1 in driving resistance to cyclin dependent Kinase 4 6 inhibitors
    Molecular Cancer Research, 2020
    Co-Authors: Seth A Wander, Eric P Winer, Ofir Cohen, Gabriela N Johnson, Jorge Buendia, Flora Luo, Joseph Geradts, Nancy U Lin, Levi A Garraway, Nikhil Wagle
    Abstract:

    Introduction: The Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i), in combination with an antiestrogen, have emerged as standard-of-care options in both the first- and subsequent-line setting for patients with metastatic hormone-receptor positive (HR+)/HER2- breast cancer. Despite their widespread use, limited insight exists into the molecular pathways governing response and resistance to these agents. Methods and Results: We performed whole-exome sequencing on metastatic tumor specimens from 59 patients with HR+/HER2- breast cancer who had received CDK4/6i-based therapy. Tumor biopsies were characterized as demonstrating sensitivity, intrinsic resistance, or acquired resistance based upon the timing of resistance, radiographic response, and duration of therapy. In contrast to prior reports indicating PIK3CA enrichment in patients receiving CDK4/6i-based therapy, alterations in PI3K were approximately evenly distributed in this cohort between sensitive and resistant biopsies (8/20, 40% vs. 21/40, 52.5%, respectively, p = 0.808 via Fisher9s exact test). Activating alterations in AKT1, however, were identified in three resistant tumor specimens, including both point mutations and amplification. In two instances where matched pretreatment sensitive biopsies and post-treatment resistance biopsies were available, an AKT1 point mutation and an AKT1 amplification, respectively, were uniquely identified in the resistant biopsy. Immunohistochemical analysis of sensitive and resistance biopsy specimens in these patients confirmed upregulation of pAKT, pS6, and pRb, indicating upregulation of the AKT signaling axis. AKT1 was introduced into multiple HR+ breast cancer cell lines in vitro (T47D, MCF7, and CAMA1) via lentiviral overexpression. Overexpression of AKT1 in these cell lines provoked significant resistance to palbociclib, abemaciclib, fulvestrant, and estrogen deprivation (via charcoal-stripped serum, CSS). AKT1-expressing cells were also resistant to the various pairwise combinations of antiestrogen and CDK4/6i. Sensitivity to estrogen deprivation and CDK4/6i could be restored by treatment with the AKT inhibitor MK2206. Conclusions: In contrast to prior reports, PIK3CA mutations did not correlate with resistance to CDK4/6 inhibition in our cohort of tumor specimens from 59 patients with metastatic HR+ breast cancer. AKT1 has emerged as a key potential mediator of resistance to both antiestrogens and CDK4/6i in vitro and in vivo. AKT1 pathway activation may serve as a potential biomarker of resistance to CDK4/6i, while novel strategies to target AKT1 may restore sensitivity to CDK4/6i-based therapy in HR+ metastatic breast cancer. Citation Format: Seth A. Wander, Ofir Cohen, Gabriela N. Johnson, Jorge Buendia, Flora Luo, Joseph Geradts, Eric P. Winer, Nancy U. Lin, Levi A. Garraway, Nikhil Wagle. Genomic sequencing of metastatic hormone-receptor positive breast cancer implicates AKT1 in driving resistance to Cyclin-Dependent Kinase 4/6 inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B23.

  • phase ib trial to evaluate safety and anti tumor activity of the akt inhibitor ipatasertib in combination with endocrine therapy and a cdk4 6 inhibitor for patients with hormone receptor positive hr her2 negative metastatic breast cancer mbc taktic
    Journal of Clinical Oncology, 2020
    Co-Authors: Seth A Wander, Dejan Juric, Jeffrey G Supko, Douglas S Micalizzi, Laura Spring, Neelima Vidula, Maureen Beeler, Karleen Habin, Elene Viscosi, Donna Fitzgerald
    Abstract:

    1066Background: The Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis sugg...

  • the genomic landscape of intrinsic and acquired resistance to cyclin dependent Kinase 4 6 inhibitors in patients with hormone receptor positive metastatic breast cancer
    Cancer Discovery, 2020
    Co-Authors: Seth A Wander, Ofir Cohen, Gabriela N Johnson, Xueqian Gong, Jorge Buendiabuendia, Maxwell R Lloyd, Dewey Kim
    Abstract:

    Mechanisms driving resistance to Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS, and AURKA-have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079.

  • cyclin dependent Kinase 4 and 6 inhibitors for hormone receptor positive breast cancer past present and future
    The Lancet, 2020
    Co-Authors: Laura Spring, Fabrice Andre, Nicholas C Turner, Seth A Wander, Beverly Moy, Aditya Bardia
    Abstract:

    Summary The development and approval of Cyclin-Dependent Kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine Kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.

  • abstract pd2 09 the genomic landscape of intrinsic and acquired resistance to cyclin dependent Kinase 4 6 inhibitors cdk4 6i in patients with hormone receptor positive hr her2 metastatic breast cancer mbc
    Cancer Research, 2020
    Co-Authors: Seth A Wander, Ofir Cohen, Gabriela N Johnson, Flora Luo, Xueqian Gong, Jorge Buendiabuendia, Maxwell R Lloyd, Dewey Kim, Pingping Mao, Karla Helvie
    Abstract:

    Background: The CDK4/6 inhibitors have emerged as standard first- or second-line regimens in combination with an antiestrogen for patients with HR+/HER2- MBC. While these agents convey significant clinical benefit in many patients, intrinsic resistance can occur and, in patients who respond, acquired resistance is unfortunately inevitable. Despite their widespread use, we have limited insight into the molecular mechanisms governing response and resistance to these agents. Methods: Whole exome sequencing (WES) was performed on metastatic tumor biopsies from 58 patients (pts) with HR+/HER2- MBC who received a CDK4/6 inhibitor with or without an antiestrogen at the Dana-Farber Cancer Institute, including 7 pts with pre/post-exposure biopsy pairs. Among these biopsies, 69.5% were characterized as resistant (intrinsic or acquired) and 30.5% were characterized as sensitive. To validate putative resistance mediators identified in patient samples, HR+/HER2- breast cancer cells were modified via CRISPR knockout or lentiviral overexpression. Sensitivity of these cells to antiestrogens and CDK4/6i was interrogated via cell-titer-glo assay. In parallel, HR+/HER2- breast cancer cells were cultured to resistance in the presence of an escalating dose of CDK4/6i. Derivative cell lines were subjected to western blotting in an effort to interrogate the putative resistance mediators identified in pts. Novel dependencies were identified in these derivative cell lines via treatment with targeted therapeutic agents in vitro. Results: WES of tumors with CDK4/6i exposure revealed candidate mechanisms of resistance including biallelic RB1 disruption (n=4, 10%) and activating events in AKT1 (n=5, 12.5%), RAS (n=4, 10%), aurora Kinase A (AURKA, n=11, 27.5%), and cyclin E2 (CCNE2, n=6, 15%). Convergent evolution toward biallelic RB1 disruption was identified in a single patient with one pre- and two post-exposure biopsies, while acquisition of AKT1 mutation and amplification was identified in two separate instances. Knockout of RB1 and overexpression of AKT1, KRAS G12D, AURKA, and CCNE2 provoked CDK4/6i and antiestrogen resistance in vitro. Breast cancer cells cultured to resistance in CDK4/6i demonstrated concordant acquisition of RB1 downregulation, RAS/ERK activation, AURKA overexpression, and CCNE2 overexpression. Derivative resistant cell lines with RB1 loss or AURKA gain demonstrated enhanced sensitivity to a novel AURKA inhibitor (LY3295668), while cells with RAS activation were highly sensitive to ERK inhibition (via LY3214996). CCNE2-overexpressing cells were highly sensitive to prexasertib, a CHEK1 inhibitor. Conclusions: The genomic landscape of resistance to CDK4/6i is heterogeneous with multiple potential mediators that play well-established roles in cell division and oncogenic signal transduction. We present novel mechanisms of clinical resistance including activation of AKT1 and RAS family oncogenes as well as amplification of AURKA and CCNE2. These drivers were able to provoke resistance to CDK4/6i in vitro. Finally, in each case, a novel dependency was identified which is readily translatable into the clinic. These results underscore the potential of next-generation sequencing as a critical tool to enable identification of resistance mediators, while also suggesting that the presence of specific genomic alterations may define new therapeutic opportunities in CDK4/6i-resistant HR+ MBC. Citation Format: Seth A. Wander, Ofir Cohen, Xueqian Gong, Gabriela N. Johnson, Jorge Buendia-Buendia, Maxwell Lloyd, Dewey Kim, Flora Luo, Pingping Mao, Karla Helvie, Kailey Kowalski, Utthara Nayar, Stephen Parsons, Ricardo Martinez, Lacey Litchfield, Xiang Ye, Chun Ping Yu, Valerie Jansen, Levi A. Garraway, Eric P. Winer, Sara M. Tolaney, Nancy U. Lin, Sean Buchanan, Nikhil Wagle. The genomic landscape of intrinsic and acquired resistance to Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) in patients with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-09.

Aditya Bardia - One of the best experts on this subject based on the ideXlab platform.

Joohyuk Sohn - One of the best experts on this subject based on the ideXlab platform.

Dejan Juric - One of the best experts on this subject based on the ideXlab platform.

  • abstract pd2 07 alpelisib letrozole in patients with pik3ca mutated hormone receptor positive hr human epidermal growth factor receptor 2 negative her2 advanced breast cancer abc previously treated with a cyclin dependent Kinase 4 6 inhibitor cdk4 6i
    Cancer Research, 2021
    Co-Authors: Hope S Rugo, Dejan Juric, Aleix Prat, Pamela Drullinsky, Nicholas C Turner, Stephen Chia, Florence Lerebours, Rafael Villanueva Vazquez, Murat Akdere, Christina Arce
    Abstract:

    Introduction: Mutations in PIK3CA, which encodes the α-isoform of phosphatidylinositol 3-Kinase (PI3Kα), occur in ~40% of patients (pts) with HR+, HER2- ABC and can contribute to endocrine resistance. Alpelisib (ALP), a PI3Kα-selective inhibitor and degrader, plus fulvestrant (FUL) demonstrated efficacy in the phase 3 SOLAR-1 trial, which included 20 pts who had prior CDK4/6i in the PIK3CA-mutant cohort. Limited clinical data are available in the post-CDK4/6i setting for PIK3CA-mutated, HR+, HER2- ABC. BYLieve (NCT03056755), an ongoing phase 2, multicenter, open-label, 3-cohort noncomparative study, is the first trial evaluating ALP + endocrine therapy (FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC who progressed on/after prior therapy, including CDK4/6i. In the prior CDK4/6i + aromatase inhibitor (AI) cohort (Cohort A), pts received ALP + FUL. With median follow-up of 11.7 months (mo), the primary endpoint in Cohort A was met—50.4% of pts were alive and without disease progression (PD) at 6 mo per local investigator assessment (n=61; 95% CI, 41.2%-59.6%). Median progression-free survival (mPFS) was 7.3 mo (n=72; 95% CI, 5.6-8.3 mo); AEs were consistent with prior observations. Now, we report on the cohort of pts who received a CDK4/6i + FUL as immediate prior therapy before enrollment (Cohort B). Methods: Daily oral treatment in Cohort B consisted of ALP 300 mg + LET 2.5 mg. Each cohort planned to enroll at least 112 pts with centrally confirmed PIK3CA mutation, based on immediate prior treatment of either a CDK4/6i + AI (Cohort A), a CDK4/6i + FUL (Cohort B), or systemic chemotherapy or endocrine therapy (which may also include prior CDK4/6i + FUL; Cohort C, follow-up ongoing). The primary endpoint, the proportion of pts with centrally confirmed PIK3CA mutation alive without PD at 6 mo per local investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, is assessed for each cohort separately and is met if the lower bound of the 95% CI is >30%. Men and premenopausal women were allowed goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly every 28 days. Results: 126 pts whose immediate prior treatment was CDK4/6i + FUL were enrolled into Cohort B: 115 had centrally confirmed PIK3CA mutations. Median follow-up was 15.0 mo (range, 1-31 mo); 58 (46.0%) had ≥2 lines of prior therapy in the metastatic setting, and 103 (81.7%) pts progressed on prior AI therapy. The primary endpoint was met with 46.1% (95% CI, 36.8%-55.6%) of pts alive without PD at 6 mo. mPFS was 5.7 mo (95% CI, 4.5-7.2 mo). The most frequent all-grade AEs (≥25%) were diarrhea (67.5%), hyperglycemia (63.5%), nausea (54.8%), decreased appetite (44.4%), stomatitis (34.1%), fatigue (31.0%), rash (31.0%), and vomiting (24.6%). Most frequent grade ≥3 AEs included hyperglycemia (25.4%), rash (9.5%), and rash maculopapular (7.9%). Incidence of AEs leading to treatment discontinuation was 14.3% (n=18); most frequent AEs leading to discontinuation were rash (4 pts, 3.2%, including rash maculopapular), fatigue, and diarrhea (3 pts, 2.4% each). Conclusion: Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of alpelisib, manageable toxicities were observed. These data suggest that alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA-mutated, HR+, HER2- ABC in the post-CDK4/6i setting. Citation Format: Hope S. Rugo, Florence Lerebours, Dejan Juric, Nicholas Turner, Stephen Chia, Pamela Drullinsky, Aleix Prat, Rafael Villanueva Vazquez, Murat Akdere, Christina Arce, Yu-Ming Shen, Eva Ciruelos. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a Cyclin-Dependent Kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-07.

  • phase ib trial to evaluate safety and anti tumor activity of the akt inhibitor ipatasertib in combination with endocrine therapy and a cdk4 6 inhibitor for patients with hormone receptor positive hr her2 negative metastatic breast cancer mbc taktic
    Journal of Clinical Oncology, 2020
    Co-Authors: Seth A Wander, Dejan Juric, Jeffrey G Supko, Douglas S Micalizzi, Laura Spring, Neelima Vidula, Maureen Beeler, Karleen Habin, Elene Viscosi, Donna Fitzgerald
    Abstract:

    1066Background: The Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis sugg...

  • a multicenter analysis of abemaciclib after progression on palbociclib in patients pts with hormone receptor positive hr her2 metastatic breast cancer mbc
    Journal of Clinical Oncology, 2019
    Co-Authors: Seth A Wander, Dejan Juric, Laura Spring, Mark L Zangardi, Andrzej Niemierko, Avinash Kambadakone, Leslie Sl Kim, Apurva Pandey, Casey Stein, Irene Kuter
    Abstract:

    1057Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) are widely used for pts with HR+/HER2- MBC. The MONARCH-1 trial of abemaciclib monotherapy in pre-treated pts demonstrated a median ...

Mario Campone - One of the best experts on this subject based on the ideXlab platform.

Cyclin-Dependent Kinase 4 - 15 days free trial to Access Experts & Abstracts