Dynamic genetic and nongenetic RAS pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy
Abstract
Bulk sequencing of relapsed tumors reveals mutations associated with resistance to cancer therapy but is insufficient to fully assess all causes of relapse. Due to inherent tumor heterogeneity, on-treatment tumor evolution may select for genetically distinct clones or shifts in malignant transcriptional states not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of a clinical trial cohort of acute myeloid leukemia (AML) patients treated on the Phase 1b clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Gilt) to characterize immunophenotypic, transcriptional, and genetic clonal evolution driving resistance. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, resistance was associated with RAS activation via multiple mechanisms including selection for RAS mutant clones, non-mutational upregulation of RAS transcriptional programs and a shift to RAS-associated monocytic AML differentiation. In an in vitro model of monocytic differentiation associated with non-mutational RAS transcriptional activation, we demonstrated that RAS pathway inhibition re-sensitized to Ven/Gilt. These data illustrate that convergent resistance pathways in patients can be activated via diverse genetic and non-genetic mechanisms. These results underscore that RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to AML monocytic differentiation and highlight RAS pathway inhibition as a viable clinical strategy to combat resistance. CT# NCT03625505
Article Details
Authors (34)
Vanessa E Kennedy
Stanford University, Stanford, California, United States
Cheryl A. C. Peretz
University of California San Francisco, San Francisco, California, United States
Anushka Walia
Brigham and Women's Hospital, Boston, Massachusetts, United States
Brenda Chyla
Abbvie, North Chicago, Illinois, United States
Yan Sun
Jason E. Hill
Astellas Pharma, Northbrook, Illinois, United States
Elaine Tran
University of California San Francisco, San Francisco, California, United States
Andrew D. Koh
University of California San Francisco, San Francisco, California, United States
Timothy T Ferng
University of California (San Francisco), San Francisco, California, United States
Samantha Pintar
University of California San Francisco, San Francisco, California, United States
Matthew Jones
Bogdan Popescu
University of California San Francisco, San Francisco, California, United States
Isabelle Lomeli
University of California San Francisco, San Francisco, California, United States
Farid Chehab
University of California, San Francisco
Natalia Murad
University of California San Francisco, San Francisco, California, United States
August John
University of California San Francisco, San Francisco, California, United States
Ritu Parna Roy
University of California San Francisco, San Francisco, California, United States
Adam B. Olshen
UCSF, San Francisco, California, United States
Christine A. Berryhill
Indiana University, Indianapolis, Indiana, United States
Christopher Davis
Indiana University School of Medicine, Department of Pediatrics, Riley Hospital for Children at IU Health
Steven Patrick Angus
Indiana University School of Medicine, Indianapolis, Indiana, United States
Jose M. Rivera
Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, United States
Alicia Meshulam
University of California, San Francisco, San Francisco, California, United States
Elliot Stieglitz
Sunil Kumar Joshi
Elie Traer
Oregon Health & Science University, Portland, Oregon, United States
Monique Dail
Illuminate Biosciences, Moss Beach, California, United States
Habib Hamidi
Jessica K Altman
Northwestern University, Chicago, Illinois, United States
Naval G Daver
University of Texas, MD Anderson Cancer Center, Houston, Texas, United States
Mark J. Levis
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
James McCloskey
John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey, United States
Alexander E. Perl
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Catherine C. Smith
University of California (San Francisco), San Francisco, California, United States