Biomarkers Predicting Venetoclax Sensitivity and Strategies for Venetoclax Combination Treatment

Abstract

BCL2 is an antiapoptotic protein commonly expressed in hematologic malignancies. Overexpression of BCL-2 is a poor prognostic factor in acute myeloid leukemia (AML). Venetoclax (ABT-199) is a highly selective BCL2 inhibitor that can induce cell death in multiple leukemia cell lines. Recently, venetoclax received an FDA breakthrough therapy designation for use in combination with hypomethylating agents in treatment-naive patients with AML who are unfit for intensive chemotherapy. However, venetoclax was only modestly effective as monotherapy in relapsed/refractory AML (19% CR/CRi). The aim of the current study is to integrate genomic and functional screen data to identify biomarkers to predict venetoclax sensitivity and resistance in AML, and to identify potential venetoclax combination treatment strategies. In this study, we investigated approximately 200 AML patient samples and correlated clinical parameters, whole exome sequence data, and RNAseq gene expression data with in vitro drug screening data (drug area under the curve (AUC)) to identify subsets of AML samples with sensitivity or resistance to venetoclax alone and in combinations with 10 small molecular inhibitors (Array-382, dasatinib, JQ-1, idelalisib, quizartinib, palbociclib, panobinostat, ruxolitinib, sorafenib, and trametinib). For gene expression, we observed that venetoclax correlated with 3 gene expression clusters (coefficient frequency: 0.94, 0.80 and 0.71 respectively) among 21 gene expression clusters in AML, associated with innate immune system, neutrophil degranulation, and interleukin-10 signaling. Among the BCL2 gene family, venetoclax AUC positively correlated with BCL2A1 (r=0.59, p In summary, we have identified that CD14 and/or CLEC7A could be used as biomarkers to predict venetoclax sensitivity in AML, and we propose to combine venetoclax and palbociclib to treat patients with a venetoclax resistant profile (high CD14/CLEC7A expression or high BCL2A1 expression, or presence of KRAS mutations). Disclosures Druker:Beta Cat: Membership on an entity9s Board of Directors or advisory committees; Fred Hutchinson Cancer Research Center: Research Funding; McGraw Hill: Patents & Royalties; Vivid Biosciences: Membership on an entity9s Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; Bristol-Meyers Squibb: Research Funding; GRAIL: Consultancy, Membership on an entity9s Board of Directors or advisory committees; ARIAD: Research Funding; Third Coast Therapeutics: Membership on an entity9s Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Monojul: Consultancy; Novartis Pharmaceuticals: Research Funding; Millipore: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity9s Board of Directors or advisory committees, Research Funding; ALLCRON: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Patient True Talk: Consultancy; Cepheid: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Henry Stewart Talks: Patents & Royalties; Celgene: Consultancy; Amgen: Membership on an entity9s Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Majeti:BioMarin: Consultancy; Forty Seven, Inc: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Tyner:Incyte: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Leap Oncology: Equity Ownership; Seattle Genetics: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Syros: Research Funding; Aptose: Research Funding; Agios: Research Funding.