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MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction

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MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction Published OnlineFirst December 20, 2013; DOI: 10.1158/2159-8290.CD-13-0235 RESEARCH ARTICLE MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction Jennifer Asmussen 1 , Elisabeth A. Lasater 6 , Cheryl Tajon 2 , Juan Oses-Prieto 3 , Young-wook Jun 4 , Barry S. Taylor 5 , 6 , 7 , Alma Burlingame 3 , Charles S. Craik 3 , and Neil P. Shah 1 , 6 , 7 ABSTRACT The clinical experience with BCR–ABL tyrosine kinase inhibitors (TKI) for the treat- ment of chronic myelogenous leukemia (CML) provides compelling evidence for oncogene addiction. Yet, the molecular basis of oncogene addiction remains elusive. Through unbi- ased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR–ABL TKI, we identifi ed 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 insuffi cient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAF V600E in melanoma cells, feedback inhibition following BCR–ABL TKI treat- ment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR–ABL-mediated oncogene addiction is facilitated by persistent high levels of MAP–ERK kinase (MEK)-dependent negative feedback. SIGNIFICANCE: We found that BCR–ABL can confer addiction in vitro by rewiring myeloid GF-R signaling through establishment of MEK-dependent negative feedback. Our fi ndings predict that deeper, more durable responses to targeted agents across a range of malignancies may be facilitated by maintaining negative feedback concurrently with oncoprotein inhibition. Cancer Discov; 4(2); 200–15. ©2013 AACR. Authors’ Affi liations: Departments of 1 Pharmaceutical Sciences and E.A. Lasater and C. Tajon contributed equally to this work. 2 3 Pharmacogenomics, Chemistry and Chemical Biology, Pharmaceutical Corresponding Author: Neil P. Shah, University of California, San Francisco, 4 5 6 Chemistry, Otolaryngology, and Epidemiology and Biostatistics; Divi- 513 Parnassus Avenue, Suite M1286, Box 1270, San Francisco, CA 94143. 7 sion of Hematology/Oncology; and Helen Diller Family Comprehensive Phone: 415-476-3303; Fax: 415-476-3725; E-mail: nshah@medicine Cancer Center, University of California, San Francisco, San Francisco, .ucsf.edu California doi: 10.1158/2159-8290.CD-13-0235 Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). © 2013 American Association for Cancer Research. 200 | CANCER DISCOVERYFEBRUARY 2014 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst December 20, 2013; DOI: 10.1158/2159-8290.CD-13-0235 INTRODUCTION Here, we sought to characterize the molecular mecha- Translational studies with small-molecule tyrosine kinase nisms that underlie BCR–ABL-mediated oncogene addiction inhibitors (TKI) in patients with chronic myelogenous leuke- in an effort to understand what makes this kinase the best- mia (CML) have convincingly demonstrated that the clinical validated target in human cancer. We applied an unbiased activity of these agents is achieved through inhibition of the kinetic quantitative phosphoproteomic analysis to CML cells intended target BCR–ABL ( 1 ). To date, the high rate of suc- transiently exposed to the BCR–ABL TKI dasatinib to identify cess associated with BCR–ABL TKIs provides the most com- candidate mediators of BCR–ABL-dependent cell survival. pelling clinical evidence for the phenomenon of “oncogene To test the importance of the observed signaling changes, addiction,” the exquisite reliance of cancer cells upon a path- we established a tissue- and species-relevant isogenic model ologically activated oncogene. Oncogene addiction enables system to molecularly characterize BCR–ABL-mediated onco- targeted therapies to effect clinical responses and simultane- gene addiction and validated our fi ndings in patient-derived ously cause little toxicity. Even in the most advanced phases cell lines. of CML, a substantial proportion of patients can achieve deep responses with BCR–ABL TKIs ( 2 ). RESULTS Our understanding of the molecular basis of oncogene addiction is poor. Sharma and colleagues proposed the term Phosphoproteomic Analysis of Pulsed “oncogenic shock” to describe the effect that activated onco- Dasatinib-Treated CML Cells Reveals Durable genes have on the balance between prosurvival and proapop- Alterations in Growth Factor Signaling Pathways totic signals. The oncogenic shock model proposes that upon Previous work demonstrated that transient exposure (20 acute inhibition of oncogene activity, a more rapid decay in minutes) of CML cell lines to clinically relevant concentra- prosurvival signals leads to a state that favors apoptosis ( 3 ). tions of dasatinib elicits apoptosis with kinetics similar to Although this model provides a useful conceptual framework continuous TKI exposure, despite evidence that BCR–ABL in which to begin to understand the phenomenon of onco- kinase activity is largely restored within 4 hours of drug gene addiction, evidence to support the oncogenic shock washout ( 12–14 ). We hypothesized that the phosphorylation model is largely circumstantial; molecular mechanisms that status of a subset of proteins must be durably altered, and lead to the proposed heightened levels of prosurvival and critical mediators of BCR–ABL-mediated cell survival would proapoptotic signals have not been well characterized. be included among this group. We therefore undertook an Over the past decade, numerous oncogenic kinases in unbiased kinetic, quantitative assessment of phosphotyrosine- a variety of cancers have been identifi ed and clinically tar- containing proteins in the patient-derived CML cell line geted, including EGF receptor (EGFR) and ALK in non– K562 transiently exposed to a high-dose pulse (HDP) of 100 small cell lung cancer, BRAF V600E in melanoma and colorectal nmol/L dasatinib using stable isotope labeling by amino cancer, and FLT3-ITD in acute myeloid leukemia (AML). acids in culture (SILAC). We successfully identifi ed 184 phos- However, efforts to extrapolate the clinical success of BCR– photyrosine residues in 126 different proteins, represent- ABL TKI therapy in CML to other malignancies have failed; ing the most comprehensive kinetic analysis of TKI-treated the majority of patients treated with other clinically active patient–derived CML cells to date (Supplementary Table S1). TKIs do not achieve responses of similar magnitude. For We compared the quantifi ed phosphotyrosine profi le before example, the selective BRAF inhibitor vemurafenib, which is TKI treatment, after 20 minutes of TKI exposure, and at 3 and approved for BRAF V600E-positive metastatic melanoma, rarely 6 hours after TKI washout ( Fig. 1A ). effects deep reductions in tumor volume ( 4 ). Interestingly, We grouped phosphotyrosine peptides based on the pattern MAP–ERK kinase (MEK) inhibitors are active in BRAFV600E - of tyrosine modifi cation following HDP dasatinib treatment. expressing cells in vitro but, unexpectedly, not in cells with Twenty-four tyrosine residues were transiently dephospho- activated receptor tyrosine kinases (RTK) that activate the rylated, 31 were gradually dephosphorylated, 46 were not RAS–MEK–ERK pathway ( 5 ). Previous studies demonstrated appreciably altered, and seven were hyperphosphorylated. that BRAF V600E establishes a high level of extracellular signal– Notably, 55 tyrosine residues were persistently dephospho- regulated kinase (ERK)–directed transcriptional output and rylated following TKI washout, and functional enrichment MEK-dependent negative feedback of growth factor receptor of these peptides revealed an overrepresentation of proteins (GF-R) signaling, whereas activated oncogenic RTKs do not. involved in GF-R signaling pathways (Supplementary Table In addition, in contrast to RTKs, BRAF V600E escapes MEK- S2). Among these were tyrosine residues from STAT5A/B, dependent negative feedback ( 6 ). ERK1/2, GAB1, and SHC1. Phosphotyrosine peptides associ- It has been postulated that effi cient bypass of BRAF kinase ated with phosphoinositide 3-kinase (PI3K)–AKT pathway inhibition through GF-R–mediated reactivation of the RAS– activation were either transiently dephosphorylated or not MAPK signaling pathway may allow melanoma cells to sur- altered ( Fig. 1B ). Several of the signaling changes identifi ed vive in the tumor microenvironment. Recent experimental in the phosphoproteomic analysis were confi rmed by West- data have demonstrated that melanoma, colorectal, and thy- ern immunoblot analysis in K562 cells and the independent roid cancer cells harboring BRAF V600E mutations are inher- patient-derived CML cell line KU812. Although tyrosine resi- ently primed to circumvent BRAF inhibition by vemurafenib dues within the PI3K–AKT pathway were not durably altered through rapid relief of negative feedback of GF-R signaling in the phosphoproteomic analysis, serine phosphorylation ( 7–11). of S6 (S235/S236) was durably altered in a time-dependent FEBRUARY 2014CANCER DISCOVERY | 201 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2014 American Association
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