Genetic determinants ofEGFR-Driven Lung Cancer Growth and Therapeutic ResponseIn Vivo

• DOI: 10.1101/2020.04.13.036921
• Publication Date: 2020-04-14T01:52:12Z
• Authors: Giorgia Foggetti; Chuan Li; Hongchen Cai; Jessica A. Hellyer; Wen-Yang Lin; Deborah Ayeni; Katherine Hastings; Jungmin Choi; Anna Wurtz; Laura Andrejka; Dylan Maghini; Nicholas Rashleigh; Stellar Levy; Robert Homer; Scott Gettinger; Maximilian Diehn; Heather A. Wakelee; Dmitri A. Petrov; Monte M. Winslow; Katerina Politi
• Keywords: Osimertinib

Abstract Cancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish impact combinations genetic alterations on tumor biology and uncover genotype-dependent effects drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative suppressor gene alterations, however extent which these contribute growth their response therapy vivo not been explored experimentally. By integrating a novel mouse model oncogenic -driven Trp53 -deficient adenocarcinoma multiplexed CRISPR–Cas9-mediated editing barcode sequencing, we quantified inactivation ten genes. Inactivation Apc , Rb1 or Rbm10 most strongly promoted growth. Unexpectedly, Lkb1 Setd2 – strongest drivers an Kras reduced These results consistent relative frequency human EGFR- KRAS adenocarcinomas. Furthermore, Keap1 reduces sensitivity tumors inhibitor osimertinib. Importantly, EGFR/TP53 mutant adenocarcinomas, KEAP1 pathway correlated decreased time tyrosine kinase treatment. Our study highlights how can have dramatically different biological consequences depending context that fitness shift upon