抑癌基因失活塑造EGFR突变型肺腺癌进展的格局及其治疗意义

Oncogenic alterations in exons encoding the kinase domain of the Epidermal Growth Factor Receptor (e.g. EGFR L858R mutations) occur frequently in lung adenocarcinomas (LUADs) and promote tumor growth. EGFR tyrosine kinase inhibitors (TKIs), like osimertinib, have greatly improved lung cancer outcomes, yet EGFR TKI resistance remains inevitable. In addition to mutations in oncogenes, co-occurring genomic alterations in tumor suppressor genes (TSGs) have emerged as core determinants of LUAD tumor fitness and therapeutic response. Moreover, recent work suggests that the oncogenic driver dictates the effect of putative TSG inactivation on the fitness landscape of tumorigenesis. To study the effects of co-occurring TSG mutations in vivo , we leveraged autochthonous, immunocompetent genetically engineered mouse models (GEMMs) of EGFR L858R-driven LUAD, in Trp53 proficient and deficient settings, carrying a conditional Cas9 allele for CRISPR-Cas9 genome editing. We investigated the effect of inactivation of 58 putative TSGs on EGFR-driven LUAD tumor growth, tumor initiation, and osimertinib sensitivity. In parallel, we also induced tumors using the same lentiviral pool in models of Kras G12D, Kras G12D; p53 -deficient, and Kras G12C-driven LUADs. In mutant EGFR-driven tumors, we identified genes that when inactivated: (i) promote tumor growth, (ii) suppress tumor growth, and (iii) reduce sensitivity to osimertinib. Inactivation of Tsc1 or Tsc2 , negative regulators of mTOR-complex signaling, and the ubiquitin ligase associated genes Cul3 and Rnf43 significantly promoted tumor growth in addition to Apc , Rbm10 , Rb1 described in a prior screen. Surprisingly, we also identified a set of genes, enriched in chromatin modifiers, that decreased tumor fitness in mutant EGFR-driven LUADs, including Crebbp and Smarca4 . Conversely, loss of these same genes did not affect the growth of Kras G12C and G12D-driven tumors, suggesting that fitness effects of gene inactivation can vary across oncogenic contexts, even within what is conventionally considered a linear signaling axis. Indeed, loss of Setd2 , Kmt2d , Ep300 , and Stk11 all had significant detrimental effects on tumor growth in an EGFR context but had significant effects promoting tumor growth in a Kras G12C context. Through this screen we also identified genes that when inactivated contribute to reduced osimertinib sensitivity in mutant EGFR-driven tumors including Nf1 , Kmt2d , and Pten in Trp53 proficient and deficient settings, whereas loss of Nf2 and Kdm6a only reduced sensitivity in a Trp53 deficient setting. These results inform the biology of tumor growth and reveal new genetic interactions in EGFR-driven LUADs with therapeutic implications.