Data from Alveolar Differentiation Drives Resistance to <i>KRAS</i> Inhibition in Lung Adenocarcinoma

Abstract

<div>Abstract<p>Lung adenocarcinoma (LUAD), commonly driven by <i>KRAS</i> mutations, is responsible for 7% of all cancer mortality. The first allele-specific <i>KRAS</i> inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples, we found inhibition of <i>KRAS</i> promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing <i>Kras</i> induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to <i>KRAS</i> inhibitors. Our results uncover an unexpected role for <i>KRAS</i> in promoting intratumoral heterogeneity and suggest that targeting alveolar differentiation may augment <i>KRAS</i>-targeted therapies in LUAD.</p>Significance:<p>Treatment resistance limits response to <i>KRAS</i> inhibitors in LUAD patients. We find LUAD residual disease following <i>KRAS</i> targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to <i>KRAS</i> inhibition, elucidating a therapeutic strategy to overcome resistance to <i>KRAS</i>-targeted therapy.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-14-2-ITI" target="_blank">This article is featured in Selected Articles from This Issue, p. 201</a></i></p></div>