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Neil P Shah - One of the best experts on this subject based on the ideXlab platform.
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mek dependent negative feedback underlies bcr abl mediated Oncogene Addiction
Cancer Discovery, 2014Co-Authors: Jennifer Asmussen, Elisabeth A Lasater, Cheryl Tajon, Juan A Osesprieto, Barry S Taylor, Alma L Burlingame, Charles S Craik, Neil P ShahAbstract:The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for Oncogene Addiction. Yet, the molecular basis of Oncogene Addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated Addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated Oncogene Addiction is facilitated by persistent high levels of MEK-dependent negative feedback.
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MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction
Cancer Discovery, 2013Co-Authors: Jennifer Asmussen, Elisabeth A Lasater, Cheryl Tajon, Barry S Taylor, Alma L Burlingame, Charles S Craik, Juan A. Oses-prieto, Neil P ShahAbstract:The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for Oncogene Addiction. Yet, the molecular basis of Oncogene Addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated Addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated Oncogene Addiction is facilitated by persistent high levels of MEK-dependent negative feedback.
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abstract 4308 a model of Oncogene Addiction bcr abl hijacks signaling through a mek dependent process and inhibits growth factor mediated signal transduction
Cancer Research, 2013Co-Authors: Jennifer Gajan, Elisabeth A Lasater, Cheryl Tajon, Charles S Craik, Neil P ShahAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome and the fusion gene BCR-ABL, which has been shown to activate key signaling pathways, including PI-3 kinase, RAS/ERK and STAT5. ABL tyrosine kinase inhibitors (TKIs) are highly effective clinical agents that inhibit downstream signaling, trigger CML cell apoptosis, and provide clinical evidence for the phenomenon of “Oncogene Addiction," whereby cell survival becomes critically dependent upon the activity of a particular Oncogene product. TKI therapy has largely failed to achieve the same degree of clinical success in other activated kinase-driven malignancies, suggesting that BCR-ABL is relatively unique in its ability to establish a state of Oncogene Addiction. Results: To dissect the mechanism by which BCR-ABL coordinates STAT5 and RAS/ERK signaling to establish a state of Oncogene Addiction, JAK2 kinase activity and RAS-GTP levels were assessed in the CML patient-derived cell line K562. Surprisingly, basal levels of RAS-GTP were low and JAK2 kinase activity was not detectable. Treatment of K562 cells with erythropoietin (EPO) only very modestly activated JAK2. Similarly, EPO treatment after one hour of BCR-ABL inhibition also failed to rescue STAT5 or RAS/ERK activation. However, with more prolonged BCR-ABL kinase inhibition, we observed a time-dependent increase in the ability of EPO to rescue STAT5 and ERK phosphorylation. After 24hrs of BCR-ABL inhibition, EPO treatment led to a significant increase in both JAK2 activation and the GTP loading of RAS relative to vehicle treated cells. These data suggest that BCR-ABL kinase activity hampers the ability of JAK2 to activate STAT5 and RAS/MAPK . Further, 24hr treatment with the MEK inhibitor PD0325901 allowed for a comparable degree of EPO-mediated JAK2 activation, suggesting that the negative regulation of JAK2 is mediated at least in part by a MEK/ERK-dependent mechanism. These observations were subsequently validated in an isogenic system utilizing TF-1 cells. Similar to the EPO/JAK2 axis in K562 cells, TF1-BCR-ABL cells exhibit attenuated GM-CSF signaling relative to control TF1-puro cells, which was restored only after prolonged BCR-ABL inhibition. Significantly, we have observed that BCR/ABL-expressing cells irreversibly commit to apoptosis before growth factor signaling is fully restored. Conclusions: Our data suggest that BCR-ABL-mediated Oncogene Addiction is a consequence of a high level of physiologic negative feedback mechanisms that dampen growth factor receptor signaling. Our findings also help reconcile recent evidence that JAK2 inhibition restores the sensitivity of CML stem/progenitor cells to ABL TKI treatment in vitro with the observation that JAK2 is completely dispensable for BCR-ABL-induced myeloid disease in mice. Citation Format: Jennifer Gajan, Elisabeth Lasater, Cheryl Tajon, Charles Craik, Neil Shah. A model of Oncogene Addiction: BCR-ABL hijacks signaling through a MEK-dependent process and inhibits growth factor-mediated signal transduction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4308. doi:10.1158/1538-7445.AM2013-4308
Dean W Felsher - One of the best experts on this subject based on the ideXlab platform.
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bim mediated apoptosis and Oncogene Addiction
Aging (Albany NY), 2016Co-Authors: Yulin Li, Anja Deutzmann, Dean W FelsherAbstract:Oncogene Addiction is a phenomenon whereby suppression of a driver Oncogene is associated with dramatic tumor regression that has been observed in experimental models and in response to targeted therapies [1]. However, the mechanism by which Oncogene inactivation induces this massive reduction in tumor burden is not clear. In tumors addicted to the MYC Oncogene, suppression of this Oncogene leads to tumor regression that is associated with a marked increase in apoptosis. This at first glance appears to be paradoxical since generally Oncogene activation, and MYC activation in particular, is associated with increased apoptosis. Recently, we have described a possible mechanism that may explain why inactivation of pro-apoptotic Oncogenes, such as MYC, induce apoptosis [2].
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Abstract IA12: Mechanisms of MYC Addiction
Molecular Cancer Research, 2015Co-Authors: Dean W FelsherAbstract:Many human cancers are caused by the activation of the MYC Oncogene. We have developed experimental transgenic mouse models to model and predict the therapeutic efficacy of targeted therapy of Oncogenes. Using the Tet system, we can conditionally regulate Oncogene expression in vivo in a temporally controlled and tissue specific manner. We have shown that many Oncogenes (MYC, RAS, BCR-ABL) induce tumorigenesis that is completely reversible upon their inactivation. We have described this phenomenon as Oncogene Addiction. Oncogene Addiction is associated with proliferative arrest, apoptosis, differentiation, cellular senescence and the shutdown of angiogenesis. The specific consequences of MYC Oncogene inactivation depend both on the genetic and cellular context. In some cases, even brief inactivation of an Oncogene can result in sustained tumor regression. In other cases, Oncogene inactivation is associated with tumor dormancy. Tumor cell intrinsic and host-dependent cell autonomous mechanisms are involved. Tumor cell intrinsic mechanisms appear to involve mechanisms that are dependent upon DNA repair processes, the regulation of protein synthesis and of cellular metabolism. Host-dependent mechanisms include the regulation of angiogenesis and immune cell elimination. In addition, tumor cells secrete autocrine factors critical to Oncogene Addiction. We have uncovered that Oncogene Addiction is both dependent upon cell autonomous and host cell dependent mechanisms. Thus, MYC via miR17-92 regulates chromatin regulatory gene products required to in a cell autonomous manner regulate cellular proliferation, survival and self-renewal programs. However, MYC through regulation of host immune mechanisms and the recruitement of CD4+ T-cells, in a host cell dependent manner, regulates the tumor microenvironment. Our experimental model systems have been employed to generate nanotechnologies and molecular imaging approaches as well as innovative therapies to respectively predict and to elicit MYC Addiction. Citation Format: Dean Felsher. Mechanisms of MYC Addiction. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA12.
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abstract a48 gene expression signatures associated with myc Oncogene Addiction in lymphoma
Molecular Cancer Research, 2015Co-Authors: Daniel C Koch, Stacey Adams, Andrew J Gentles, Benedict Anchang, Delaney K Sullivan, Sylvia K Plevritis, Dean W FelsherAbstract:c-MYC is a bHLH transcription factor that heterodimerizes with MAX to form an active transcription factor complex that binds to promoter regions across the genome. MYC is a potent Oncogene that promotes tumorigenesis in many cell types. Several studies have shown that tumor cells can be dependent on proto-Oncogenes such as MYC, a state called “Oncogene Addiction.” Recent findings have revealed that c-myc amplifies active gene programs, and our group has previously identified a unique MYC transcriptional signature. In an effort to understand how MYC regulates discrete transcriptional programs across the genome we searched for potential cofactors that coordinate with MYC. Using computational approaches we examined several publically available human data sets as well as our own conditional MYC murine model for potential co-factor interactions. We have determined that several Jumonji family members coordinate with MYC expression. Currently, we are using CRISPR/Cas9 mediated disruption of target genes in murine cells to investigate whether these genes have a casual role in MYC Oncogene Addiction. Citation Format: Daniel Koch, Stacey Adams, Andrew Gentles, Benedict Anchang, Delaney Sullivan, Sylvia Plevritis, Dean Felsher. Gene expression signatures associated with MYC Oncogene Addiction in lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A48.
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abstract pr13 mir 17 92 mediates myc Oncogene Addiction
Molecular Cancer Research, 2015Co-Authors: Yulin Li, Peter S Choi, Stephanie C Casey, David L Dill, Dean W FelsherAbstract:The MYC Oncogene is frequently overexpressed in human cancers. MYC can transcriptionally and translationally regulate the expression of thousands of genes. However, it was unclear which specific genes are responsible for MYC to maintain a neoplastic state. The microRNA cluster miR-17-92 is a major MYC target gene known to regulate proliferation, survival, and angiogenesis, which are several of the key phenotypes associated with MYC Oncogene Addiction. The resemblance of biological functions between MYC and miR-17-92 thus evoked the hypothesis that miR-17-92 is causally responsible for at least part of the mechanism by which MYC maintains a neoplastic state. We have found that miR-17-92 regulates multiple histone modifiers, such as Sin3b, Hbp1, Suv420h1, and Btg1, as well as the apoptosis regulator Bim, to maintain autonomous proliferation, survival, and self-renewal of MYC-driven tumors. Conversely, MYC inactivation downregulates the expression of miR-17-92 and results in the loss of neoplastic features as a consequence of restoration of senescence, apoptosis, and differentiation. Thus, the expression of miR-17-92 can dictate the cellular fates of MYC-driven tumors between survival versus apoptosis and proliferation versus senescence. Our findings provide a mechanistic insight into why tumors are dependent on or addicted to MYC. Citation Format: Yulin Li, Peter S. Choi, Stephanie C. Casey, David L. Dill, Dean W. Felsher. miR-17-92 mediates MYC Oncogene Addiction. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR13.
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Oncogene Addiction resetting the safety switch
Oncotarget, 2014Co-Authors: Yulin Li, Peter S Choi, Dean W FelsherAbstract:The term “Oncogene Addiction” was first coined by Dr. Bernard Weinstein to describe the exquisite dependency of tumor cells on the expression of specific Oncogenes for their relentless proliferation and survival [1]. Since cancers generally have accumulated multiple genetic and epigenetic abnormalities, it is surprising that they can remain dependent on any particular oncogenic driver. This “Achilles’ heel” of cancer has been widely exploited by targeted therapy of many human cancers, such as imatinib for BCR-ABL-driven leukemia, crizotinib for leukemia with FLT3-ITD mutations, gefitinib for lung adenocarcinoma with EGFR mutations, and vemurafenib for melanomas with B-RAF mutations. However, the mechanism of Oncogene Addiction is not clear. Several non-mutually exclusive mechanisms for Oncogene Addiction have been proposed, such as synthetic lethality, genetic streamlining, oncogenic shock, and the safety switch model. In the synthetic lethality model, some mutations that develop during cancer evolution are either neutral or adaptive only in the presence of the driver Oncogene [2]. However, these same mutations are deleterious to the cancer cells in the absence of the driver Oncogene, rendering the cancer cells unfit for survival. In the genetic streamlining model, the cancer cells are rewired by the dominant oncogenic driver and lose the cellular functions that are not essential for survival and proliferation [3]. Thus, the tumors will collapse once the dominant signaling pathway upon which cancer cells are highly dependent is suppressed. The oncogenic shock model posits that there is a differential decay of the pro-survival and pro- apoptotic signals upon the inactivation of an Oncogene. This differential decay results in a vulnerable window, causing the cell to irreversibly undergo apoptosis [4]. Previously, we also proposed the cellular safety switch model. We suggested that the inactivation of the driver Oncogene restores the normal cellular safety switch, and thus leads to proliferative arrest, apoptosis, and/or cellular senescence [5, 6]. However, a molecular mechanism has not been elucidated for any of these models. Now we have uncovered the molecular mechanism underlying the cellular safety switch model in MYC- induced tumors [7]. MYC inactivation is associated with the loss of many of the hallmark features of tumorigenesis and results in proliferative arrest, apoptosis, differentiation, and senescence, as well as the shutdown of angiogenesis. These phenotypes induced by MYC inactivation are surprisingly similar to those resulting from the loss in function of miR-17-92, a MYC target gene known to regulate multiple aspects of tumorigenesis, such as proliferation, survival, and angiogenesis. Therefore, we speculated that miR-17-92 could mediate MYC Oncogene Addiction. Indeed, we found miR-17-92 expression rescued many of the phenotypes associated with MYC inactivation. Furthermore, we discovered that miR-17-92 can target several histone modifiers, such as Sin3 transcription regulator family member B (Sin3b), high mobility group box transcription factor 1 (Hbp1), suppressor of variegation 4–20 homolog 1 (Suv420h1), and B cell translocation gene 1 (Btg1), as well as the apoptosis mediator Bcl2-like 11 (Bcl2l11, also known as Bim). Sin3b and Hbp1 coordinately recruit histone deacetylases to downregulate the expression of proliferation-related genes, resulting in cell cycle exit and senescence. Suv420h1 can regulate chromatin compaction and senescence by methylating histone H4 lysine 20. Btg1 can also regulate chromatin state, senescence, and differentiation by activating protein arginine methyltransferase 1 (Prmt1) to methylate histone H4 arginine 3. Thus, through coordinately regulating multiple epigenetic programs, these histone modifiers induce proliferative arrest and senescence upon MYC inactivation. By modulating the expression of these histone modifiers and the apoptosis regulator, Bim, miR-17-92 can block the normal cellular safety switch and sustain the neoplastic state of MYC- driven tumors. Upon the inactivation of MYC, the downregulation of miR-17-92 results in the induction of these target genes, which can drive senescence, apoptosis, and differentiation. Hence, MYC inactivation appears to reset the cellular safety switch and results in tumor collapse [7]. Although we observed our results in MYC-induced tumors, we speculate that other oncogenic drivers are likely to operate through similar if not identical mechanisms. For example, we have observed that suppression of RAS or BCR-ABL similarly activates senescence and apoptosis programs. This safety switch model supported by our experimental observations provides a possible general mechanistic explanation for the phenomenon of Oncogene Addiction.
Cheryl Tajon - One of the best experts on this subject based on the ideXlab platform.
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mek dependent negative feedback underlies bcr abl mediated Oncogene Addiction
Cancer Discovery, 2014Co-Authors: Jennifer Asmussen, Elisabeth A Lasater, Cheryl Tajon, Juan A Osesprieto, Barry S Taylor, Alma L Burlingame, Charles S Craik, Neil P ShahAbstract:The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for Oncogene Addiction. Yet, the molecular basis of Oncogene Addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated Addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated Oncogene Addiction is facilitated by persistent high levels of MEK-dependent negative feedback.
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MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction
Cancer Discovery, 2013Co-Authors: Jennifer Asmussen, Elisabeth A Lasater, Cheryl Tajon, Barry S Taylor, Alma L Burlingame, Charles S Craik, Juan A. Oses-prieto, Neil P ShahAbstract:The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for Oncogene Addiction. Yet, the molecular basis of Oncogene Addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated Addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated Oncogene Addiction is facilitated by persistent high levels of MEK-dependent negative feedback.
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abstract 4308 a model of Oncogene Addiction bcr abl hijacks signaling through a mek dependent process and inhibits growth factor mediated signal transduction
Cancer Research, 2013Co-Authors: Jennifer Gajan, Elisabeth A Lasater, Cheryl Tajon, Charles S Craik, Neil P ShahAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome and the fusion gene BCR-ABL, which has been shown to activate key signaling pathways, including PI-3 kinase, RAS/ERK and STAT5. ABL tyrosine kinase inhibitors (TKIs) are highly effective clinical agents that inhibit downstream signaling, trigger CML cell apoptosis, and provide clinical evidence for the phenomenon of “Oncogene Addiction," whereby cell survival becomes critically dependent upon the activity of a particular Oncogene product. TKI therapy has largely failed to achieve the same degree of clinical success in other activated kinase-driven malignancies, suggesting that BCR-ABL is relatively unique in its ability to establish a state of Oncogene Addiction. Results: To dissect the mechanism by which BCR-ABL coordinates STAT5 and RAS/ERK signaling to establish a state of Oncogene Addiction, JAK2 kinase activity and RAS-GTP levels were assessed in the CML patient-derived cell line K562. Surprisingly, basal levels of RAS-GTP were low and JAK2 kinase activity was not detectable. Treatment of K562 cells with erythropoietin (EPO) only very modestly activated JAK2. Similarly, EPO treatment after one hour of BCR-ABL inhibition also failed to rescue STAT5 or RAS/ERK activation. However, with more prolonged BCR-ABL kinase inhibition, we observed a time-dependent increase in the ability of EPO to rescue STAT5 and ERK phosphorylation. After 24hrs of BCR-ABL inhibition, EPO treatment led to a significant increase in both JAK2 activation and the GTP loading of RAS relative to vehicle treated cells. These data suggest that BCR-ABL kinase activity hampers the ability of JAK2 to activate STAT5 and RAS/MAPK . Further, 24hr treatment with the MEK inhibitor PD0325901 allowed for a comparable degree of EPO-mediated JAK2 activation, suggesting that the negative regulation of JAK2 is mediated at least in part by a MEK/ERK-dependent mechanism. These observations were subsequently validated in an isogenic system utilizing TF-1 cells. Similar to the EPO/JAK2 axis in K562 cells, TF1-BCR-ABL cells exhibit attenuated GM-CSF signaling relative to control TF1-puro cells, which was restored only after prolonged BCR-ABL inhibition. Significantly, we have observed that BCR/ABL-expressing cells irreversibly commit to apoptosis before growth factor signaling is fully restored. Conclusions: Our data suggest that BCR-ABL-mediated Oncogene Addiction is a consequence of a high level of physiologic negative feedback mechanisms that dampen growth factor receptor signaling. Our findings also help reconcile recent evidence that JAK2 inhibition restores the sensitivity of CML stem/progenitor cells to ABL TKI treatment in vitro with the observation that JAK2 is completely dispensable for BCR-ABL-induced myeloid disease in mice. Citation Format: Jennifer Gajan, Elisabeth Lasater, Cheryl Tajon, Charles Craik, Neil Shah. A model of Oncogene Addiction: BCR-ABL hijacks signaling through a MEK-dependent process and inhibits growth factor-mediated signal transduction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4308. doi:10.1158/1538-7445.AM2013-4308
Charles S Craik - One of the best experts on this subject based on the ideXlab platform.
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mek dependent negative feedback underlies bcr abl mediated Oncogene Addiction
Cancer Discovery, 2014Co-Authors: Jennifer Asmussen, Elisabeth A Lasater, Cheryl Tajon, Juan A Osesprieto, Barry S Taylor, Alma L Burlingame, Charles S Craik, Neil P ShahAbstract:The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for Oncogene Addiction. Yet, the molecular basis of Oncogene Addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated Addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated Oncogene Addiction is facilitated by persistent high levels of MEK-dependent negative feedback.
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MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction
Cancer Discovery, 2013Co-Authors: Jennifer Asmussen, Elisabeth A Lasater, Cheryl Tajon, Barry S Taylor, Alma L Burlingame, Charles S Craik, Juan A. Oses-prieto, Neil P ShahAbstract:The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for Oncogene Addiction. Yet, the molecular basis of Oncogene Addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated Addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated Oncogene Addiction is facilitated by persistent high levels of MEK-dependent negative feedback.
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abstract 4308 a model of Oncogene Addiction bcr abl hijacks signaling through a mek dependent process and inhibits growth factor mediated signal transduction
Cancer Research, 2013Co-Authors: Jennifer Gajan, Elisabeth A Lasater, Cheryl Tajon, Charles S Craik, Neil P ShahAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome and the fusion gene BCR-ABL, which has been shown to activate key signaling pathways, including PI-3 kinase, RAS/ERK and STAT5. ABL tyrosine kinase inhibitors (TKIs) are highly effective clinical agents that inhibit downstream signaling, trigger CML cell apoptosis, and provide clinical evidence for the phenomenon of “Oncogene Addiction," whereby cell survival becomes critically dependent upon the activity of a particular Oncogene product. TKI therapy has largely failed to achieve the same degree of clinical success in other activated kinase-driven malignancies, suggesting that BCR-ABL is relatively unique in its ability to establish a state of Oncogene Addiction. Results: To dissect the mechanism by which BCR-ABL coordinates STAT5 and RAS/ERK signaling to establish a state of Oncogene Addiction, JAK2 kinase activity and RAS-GTP levels were assessed in the CML patient-derived cell line K562. Surprisingly, basal levels of RAS-GTP were low and JAK2 kinase activity was not detectable. Treatment of K562 cells with erythropoietin (EPO) only very modestly activated JAK2. Similarly, EPO treatment after one hour of BCR-ABL inhibition also failed to rescue STAT5 or RAS/ERK activation. However, with more prolonged BCR-ABL kinase inhibition, we observed a time-dependent increase in the ability of EPO to rescue STAT5 and ERK phosphorylation. After 24hrs of BCR-ABL inhibition, EPO treatment led to a significant increase in both JAK2 activation and the GTP loading of RAS relative to vehicle treated cells. These data suggest that BCR-ABL kinase activity hampers the ability of JAK2 to activate STAT5 and RAS/MAPK . Further, 24hr treatment with the MEK inhibitor PD0325901 allowed for a comparable degree of EPO-mediated JAK2 activation, suggesting that the negative regulation of JAK2 is mediated at least in part by a MEK/ERK-dependent mechanism. These observations were subsequently validated in an isogenic system utilizing TF-1 cells. Similar to the EPO/JAK2 axis in K562 cells, TF1-BCR-ABL cells exhibit attenuated GM-CSF signaling relative to control TF1-puro cells, which was restored only after prolonged BCR-ABL inhibition. Significantly, we have observed that BCR/ABL-expressing cells irreversibly commit to apoptosis before growth factor signaling is fully restored. Conclusions: Our data suggest that BCR-ABL-mediated Oncogene Addiction is a consequence of a high level of physiologic negative feedback mechanisms that dampen growth factor receptor signaling. Our findings also help reconcile recent evidence that JAK2 inhibition restores the sensitivity of CML stem/progenitor cells to ABL TKI treatment in vitro with the observation that JAK2 is completely dispensable for BCR-ABL-induced myeloid disease in mice. Citation Format: Jennifer Gajan, Elisabeth Lasater, Cheryl Tajon, Charles Craik, Neil Shah. A model of Oncogene Addiction: BCR-ABL hijacks signaling through a MEK-dependent process and inhibits growth factor-mediated signal transduction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4308. doi:10.1158/1538-7445.AM2013-4308
Elisabeth A Lasater - One of the best experts on this subject based on the ideXlab platform.
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mek dependent negative feedback underlies bcr abl mediated Oncogene Addiction
Cancer Discovery, 2014Co-Authors: Jennifer Asmussen, Elisabeth A Lasater, Cheryl Tajon, Juan A Osesprieto, Barry S Taylor, Alma L Burlingame, Charles S Craik, Neil P ShahAbstract:The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for Oncogene Addiction. Yet, the molecular basis of Oncogene Addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated Addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated Oncogene Addiction is facilitated by persistent high levels of MEK-dependent negative feedback.
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MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction
Cancer Discovery, 2013Co-Authors: Jennifer Asmussen, Elisabeth A Lasater, Cheryl Tajon, Barry S Taylor, Alma L Burlingame, Charles S Craik, Juan A. Oses-prieto, Neil P ShahAbstract:The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for Oncogene Addiction. Yet, the molecular basis of Oncogene Addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated Addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated Oncogene Addiction is facilitated by persistent high levels of MEK-dependent negative feedback.
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abstract 4308 a model of Oncogene Addiction bcr abl hijacks signaling through a mek dependent process and inhibits growth factor mediated signal transduction
Cancer Research, 2013Co-Authors: Jennifer Gajan, Elisabeth A Lasater, Cheryl Tajon, Charles S Craik, Neil P ShahAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome and the fusion gene BCR-ABL, which has been shown to activate key signaling pathways, including PI-3 kinase, RAS/ERK and STAT5. ABL tyrosine kinase inhibitors (TKIs) are highly effective clinical agents that inhibit downstream signaling, trigger CML cell apoptosis, and provide clinical evidence for the phenomenon of “Oncogene Addiction," whereby cell survival becomes critically dependent upon the activity of a particular Oncogene product. TKI therapy has largely failed to achieve the same degree of clinical success in other activated kinase-driven malignancies, suggesting that BCR-ABL is relatively unique in its ability to establish a state of Oncogene Addiction. Results: To dissect the mechanism by which BCR-ABL coordinates STAT5 and RAS/ERK signaling to establish a state of Oncogene Addiction, JAK2 kinase activity and RAS-GTP levels were assessed in the CML patient-derived cell line K562. Surprisingly, basal levels of RAS-GTP were low and JAK2 kinase activity was not detectable. Treatment of K562 cells with erythropoietin (EPO) only very modestly activated JAK2. Similarly, EPO treatment after one hour of BCR-ABL inhibition also failed to rescue STAT5 or RAS/ERK activation. However, with more prolonged BCR-ABL kinase inhibition, we observed a time-dependent increase in the ability of EPO to rescue STAT5 and ERK phosphorylation. After 24hrs of BCR-ABL inhibition, EPO treatment led to a significant increase in both JAK2 activation and the GTP loading of RAS relative to vehicle treated cells. These data suggest that BCR-ABL kinase activity hampers the ability of JAK2 to activate STAT5 and RAS/MAPK . Further, 24hr treatment with the MEK inhibitor PD0325901 allowed for a comparable degree of EPO-mediated JAK2 activation, suggesting that the negative regulation of JAK2 is mediated at least in part by a MEK/ERK-dependent mechanism. These observations were subsequently validated in an isogenic system utilizing TF-1 cells. Similar to the EPO/JAK2 axis in K562 cells, TF1-BCR-ABL cells exhibit attenuated GM-CSF signaling relative to control TF1-puro cells, which was restored only after prolonged BCR-ABL inhibition. Significantly, we have observed that BCR/ABL-expressing cells irreversibly commit to apoptosis before growth factor signaling is fully restored. Conclusions: Our data suggest that BCR-ABL-mediated Oncogene Addiction is a consequence of a high level of physiologic negative feedback mechanisms that dampen growth factor receptor signaling. Our findings also help reconcile recent evidence that JAK2 inhibition restores the sensitivity of CML stem/progenitor cells to ABL TKI treatment in vitro with the observation that JAK2 is completely dispensable for BCR-ABL-induced myeloid disease in mice. Citation Format: Jennifer Gajan, Elisabeth Lasater, Cheryl Tajon, Charles Craik, Neil Shah. A model of Oncogene Addiction: BCR-ABL hijacks signaling through a MEK-dependent process and inhibits growth factor-mediated signal transduction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4308. doi:10.1158/1538-7445.AM2013-4308
