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

Male 0301 basic medicine Acrylamides 0303 health sciences Aniline Compounds Lung Neoplasms Adenocarcinoma of Lung Antineoplastic Agents 3. Good health ErbB Receptors Disease Models, Animal Mice 03 medical and health sciences Animals Humans Female
DOI: 10.1101/2020.04.13.036921 Publication Date: 2020-04-14T01:52:12Z
ABSTRACT
AbstractCancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma,EGFRmutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapyin vivohas not been explored experimentally. By integrating a novel mouse model of oncogenicEGFR-drivenTrp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation ofApc,Rb1, orRbm10most strongly promoted tumor growth. Unexpectedly, inactivation ofLkb1orSetd2 –which are the strongest drivers of tumor growth in an oncogenicKras-driven model – reducedEGFR-driven tumor growth. These results are consistent with the relative frequency of these tumor suppressor gene alterations in humanEGFR-andKRAS-driven lung adenocarcinomas. Furthermore,Keap1inactivation reduces the sensitivity ofEGFR-drivenTrp53-deficient tumors to the EGFR inhibitor osimertinib. Importantly, in humanEGFR/TP53mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.
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