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Combined C-Met/Trk Inhibition Overcomes Resistance to CDK4/6 Inhibitors In Author Manuscript Published OnlineFirst on May 29, 2018; DOI: 10.1158/0008-5472.CAN-17-3124 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in Glioblastoma Inan Olmez1,*, Ying Zhang2, Laryssa Manigat1, Mouadh Benamar3,4, Breanna Brenneman1, Ichiro Nakano5, Jakub Godlewski6, Agnieszka Bronisz6, Jeongwu Lee7, Tarek Abbas3,4, Roger Abounader2, and Benjamin Purow1 1Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA. 2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA. 3Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA. 4Department of Radiation Oncology, University of Virginia, Charlottesville, VA 22908, USA. 5Department of Neurosurgery, University of Alabama, Birmingham, AL 35233, USA. 6Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA. 7Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Running title: c-Met/Trk activation drives resistance to CDK4/6 inhibition *Corresponding Author: Inan Olmez, M.D., University of Virginia, Old Medical School, Room 4885, 21 Hospital Drive, Charlottesville, VA 22908, USA. P: 434-892-6664, F: 434-982-4467, [email protected] or [email protected] Disclosure of Potential Conflicts of Interest: Authors declare no competing financial interests. Word count: 4080 Number of figures and tables: 5 figures and 1 table 1 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2018; DOI: 10.1158/0008-5472.CAN-17-3124 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM. We show that both c-Met and TrkA-B pathways transactivate each other, and targeting both pathways simultaneously results in more efficient pathway suppression. Mechanistically, inhibition of CDK4/6 drove NF-κB-mediated upregulation of hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) that in turn activated both c-Met and TrkA-B pathways. Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c- Met/Trk with CDK4/6 should be considered in future clinical trials. Keywords: CDK4/6, c-Met, TrkA, TrkB, Glioblastoma, altiratinib, abemaciclib Statement of Significance: CDK4/6 inhibition in glioblastoma activates the c-Met and TrkA-B pathways mediated by NF-κB and can be reversed by a dual c-Met/Trk inhibitor. 2 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2018; DOI: 10.1158/0008-5472.CAN-17-3124 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Glioblastoma (GBM) is the most common primary brain malignancy and one of the deadliest human cancers (1). Despite diagnostic and therapeutic advances, the prognosis remains extremely poor, with median survival of 15-18 months from the initial diagnosis (2). Therefore, alternative therapeutic options are urgently needed. Intratumoral molecular heterogeneity and adaptability are key hallmarks of GBM, and these may play a crucial role in the development of resistance to targeted therapies. GBM harbors a small subset of glioma-initiating cells (GICs) that may promote heterogeneity and adaptability and contribute to therapeutic failure (3). Notably, a recent study revealed that GICs drive adaptive changes in protein signaling within 2.5 days from the initiation of monotherapy (4). Thus, the identification of pathways activated in response to single-agent treatment (e.g. through bioinformatic, genetic or pharmacological screening approaches) may represent a novel strategy for the development of rational combination therapies to overcome these early adaptive changes. Like other cancer cells, mechanisms regulating cell cycle progression are deregulated in GBM, leading to enhanced cell cycle re-entry and proliferation. Analysis of The Cancer Genome Atlas (TCGA) database revealed that the CDK4/6-Rb-E2F axis is deregulated in about 80% of GBMs, with lesions including loss of p16INK4a, providing an opportunity for the development of effective therapies through targeting the cell cycle in GBM (5,6). CDK4/6 inhibitors are the sole group of cell cycle inhibitors now in the clinic, with FDA approval for hormone receptor-positive breast cancers and tumors with loss of p16INK4a or increased cyclin D1 (7,8). While a few reports from preclinical GBM models have suggested that CDK4/6 inhibitors have single-agent activity against GBM (9-11), it is now evident that CDK4/6 inhibitors drive rapid genetic and non- 3 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2018; DOI: 10.1158/0008-5472.CAN-17-3124 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. genetic changes leading to therapeutic failure (12,13). Therefore, combination therapies will be necessary to overcome resistance to CDK4/6 inhibitors. In addition to the CDK4/6-Rb-E2F axis, TCGA data have suggested that receptor tyrosine kinase (RTK) signaling pathways are hyperactivated in 80-90% of GBMs through genetic and non- genetic modifications—thus identifying another crucial target for GBM (14,15). In addition to mutations/amplifications in epidermal growth factor receptor (EGFR), one of the most common genetic abnormalities in GBM, other RTKs such as vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor alpha (PDGFRA), and c-Met have been shown to be altered to promote growth, treatment resistance, and recurrence (6,16). Therefore, we aimed to establish an effective combination regimen against GBM via targeting the two commonly altered signaling pathways—the CDK4/6-Rb-E2F axis and RTKs. To identify RTKs driving resistance upon CDK4/6 inhibition, we used a phospho-RTK protein array to screen for reactive changes in the activation status of various RTKs. Surprisingly, we found that strong increases in RTK signaling were observed in only two RTKs, c-Met and TrkA- B, with a few other RTKs activated to a lesser extent. Based on these findings, we hypothesized that combined activation of the c-Met/TrkA-B signaling pathways is a rapid mechanism for cancer resistance to CDK4/6 inhibition, and that the dual inhibition of c-Met/TrkA-B may overcome this resistance. Our results demonstrate that the CDK4/6 inhibitor abemaciclib and c- Met/TrkA-B inhibitor altiratinib synergistically suppress GBM, with potential relevance for other cancers as well. 4 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2018; DOI: 10.1158/0008-5472.CAN-17-3124 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. MATERIALS AND METHODS Cell culture, cell viability detection, reagents, and self-renewal assays Primary GIC lines were received from Jakub Godlewski (Brigham and Women’s Hospital) and Jeongwu Lee (Cleveland Clinic) in 2014 and have been published previously (17,18). We verified the human identity of these cell lines with short tandem repeat profiling prior to experimentation. Established stem cell markers such as SOX2, CD133, OLIG2, and CD44 were used for validating the GICs. All cell lines tested negative for mycoplasma contamination by PCR and repeat testing was done every five weeks. Low passage number (<10) for each line was ensured throughout the study by restarting with an early-passage sample every four weeks. GIC lines were cultured as floating neurospheres using neurobasal media supplemented with glutamine, N2 (ThermoFisher), B27 (ThermoFisher), EGF (20 ng/ml, R&D), and FGF (20 ng/ml, R&D). For in vitro experiments, neurospheres were dissolved into individual cells using ethylenediaminetetraacetic acid (EDTA) 0.02% (Lonza) and were seeded onto laminin- (Corning) coated plates. For self-renewal assays, ultra-low attachment plates (Corning) were used. Neurospheres were counted following drug treatments and data were interpreted as described previously (19). Cell viability was measured with both alamarBlue (ThermoFisher Scientific) and Trypan Blue exclusion/cell counting
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