Oral and Poster Abstracts
605. Molecular Pharmacology, Drug Resistance—Lymphoid and Other Diseases: Poster I
Biological, Diseases, Mantle Cell Lymphoma, Therapies, Combinations, Non-Hodgkin Lymphoma, DLBCL, Biological Processes, Technology and Procedures, Lymphoid Malignancies, genomics, NGS, RNA sequencing, pathways, proteomics
Michelle Wang, BSE1*, Tao Li, MD2*, Yuan Ren, Ph.D.3*, Bijal Shah, MD1, Tint Lwin, MD, PhD4*, Jing Gao, PhD5*, Kenneth H. Shain, MD, PhD 6, Wei Zhang, PhD7*, Xiaohong Zhao, MD, PhD1* and Jianguo Tao, MD, PhD1
1Moffitt Cancer Center, Tampa, FL
2Moffitt Cancer Center & Research Institute, Tampa, FL
3H. Lee Moffitt Cancer Center, Tampa, FL
4H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
5Moffitt Cancer Center, Tampa
6Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Saint Petersburg, FL
7Univeristy of Central Florida, Orlando, FL
Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are aggressive hematologic malignancies characterized by the accumulation of lymphoid cells defective in cell apoptosis biology and function. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins are pivotal regulators of the mitochondrial apoptotic pathway and genetic aberrations in these genes are associated with lymphomagenesis and chemotherapeutic resistance. Notably, the anti-apoptotic myeloid cell leukemia 1 (MCL-1) protein is recurrently highly expressed in various kinds of non-Hodgkin's B-cell lymphomas and promotes the survival of lymphoma cells by counteracting pro-apoptotic protein activity. Collectively, these data support the hypothesis that MCL-1 plays a central role in B-cell lymphoma progression and drug resistance. Pharmacologically targeting MCL-1, therefore, represents an attractive strategy to combat these lymphomas. However, previous clinical and pre-clinical data suggest that treatment with single agent anti-BCL-2 family member therapy is associated with rapid acquisition of resistance. To this end, there is a great need to develop and apply selective small molecule MCL-1 inhibitors as part of a first-line therapy or upon emergence of tumor resistance characterized by upregulation of MCL-1 for lymphoma therapy. Here, we exploited the MCL-1 dependency in MCL and DLBCL by implementing pharmacogenomic and chemical proteomic approaches to investigate the molecular drug response and resistance mechanism to MCL-1 inhibitors. In anticipation of the evolution of MCL-1 inhibitor resistance, we modeled MCL-1 inhibitor resistance mechanisms by developing S63845 resistant lines with high doses of S63845 treatment for an extended period in MCL, DLBCL and MCL-derived lines. RNA sequencing and chemical proteomics on paired parental and resistant cells demonstrated that transcriptome and kinome reprograming linked to the MEK and ERK pathways contribute to MCL-1 inhibitor resistance via regulation of the BCL-2 family profile (BCL-2 and BIM), and as such, represent a novel targetable vulnerability in MCL-1 inhibitor resistant lymphoma. Additional analyses revealed synergistic activity of MCL-1 inhibitors (S63845, AZD5991) in combinations with inhibitors of MEK (Trametinib), ERK (SCH772984) and BCR (Ibrutinib) in MCL-1 inhibitor resistant MCL/DLBCL lines and primary samples. These results provide a strong rationale for further evaluation of MCL-1 inhibitor in combination with established therapy in the clinical setting and highlight a potential strategy for overcoming MCL-1 inhibitor resistance.
*signifies non-member of ASH
Disclosures: Shah: NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Kite/Gilead, Jazz, Incyte: Research Funding; Moffitt Cancer Center: Current Employment; Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria. Shain: AbbVie: Research Funding; GlaxoSmithKline: Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive: Consultancy, Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau.