Open AccessKeap1 mutation renders lung adenocarcinomas dependent on Slc33a1
Author(s) -
Rodrigo Romero,
Francisco J. SánchezRivera,
Peter M.K. Westcott,
Kim L. Mercer,
Arjun Bhutkar,
Alexander Muir,
Tania J. González Robles,
Swanny Lamboy Rodríguez,
Laura Z. Liao,
Sheng Rong Ng,
Leanne Li,
Caterina I. Colón,
Santiago Naranjo,
Mary C. Beytagh,
Caroline A. Lewis,
Peggy P. Hsu,
Roderick T. Bronson,
Matthew G. Vander Heiden,
Tyler Jacks
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-0071-1
Subject(s) - druggability , crispr , mutant , biology , genetics , gene , computational biology , genome editing , genome , genetic screen , mutation , cancer research
Approximately 20-30% of human lung adenocarcinomas (LUAD) harbor loss-of-function (LOF) mutations in Kelch-like ECH Associated-Protein 1 ( KEAP1 ), which lead to hyperactivation of the nuclear factor, erythroid 2-like 2 (NRF2) antioxidant pathway and correlate with poor prognosis 1-3 . We previously showed that Keap1 mutation accelerates KRAS-driven LUAD and produces a marked dependency on glutaminolysis 4 . To extend the investigation of genetic dependencies in the context of Keap1 mutation, we performed a druggable genome CRISPR-Cas9 screen in Keap1 -mutant cells. This analysis uncovered a profound Keap1 mutant-specific dependency on solute carrier family 33 member 1 ( Slc33a1 ), an endomembrane-associated protein with roles in autophagy regulation 5 , as well as a series of functionally-related genes implicated in the unfolded protein response. Targeted genetic and biochemical experiments using mouse and human Keap1 -mutant tumor lines, as well as preclinical genetically-engineered mouse models (GEMMs) of LUAD, validate Slc33a1 as a robust Keap1 -mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to Slc33a1 dependency. Overall, our study provides a strong rationale for stratification of patients harboring KEAP1 -mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with GEMMs to identify and validate genotype-specific therapeutic targets.