Data from Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify <i>Kras</i>-Mutant Lung Cancers

Abstract

<div>Abstract<p>Most non–small cell lung cancers (NSCLC) contain nontargetable mutations, including <i>KRAS, TP53</i>, or <i>STK11/LKB1</i> alterations. By coupling <i>ex vivo</i> drug sensitivity profiling with <i>in vivo</i> drug response studies, we aimed to identify drug vulnerabilities for these NSCLC subtypes. Primary adenosquamous carcinoma (ASC) or adenocarcinoma (AC) cultures were established from <i>Kras<sup>G12D/+</sup>;Lkb1<sup>fl/fl</sup></i> (KL) tumors or AC cultures from <i>Kras<sup>G12D/+</sup>;p53<sup>fl/fl</sup></i> (KP) tumors. Although <i>p53</i>-null cells readily propagated as conventional cultures, <i>Lkb1</i>-null cells required conditional reprograming for establishment. Drug response profiling revealed short-term response to MEK inhibition, yet long-term clonogenic assays demonstrated resistance, associated with sustained or adaptive activation of receptor tyrosine kinases (RTK): activation of ERBBs in KL cultures, or FGFR in AC cultures. Furthermore, pan-ERBB inhibition reduced the clonogenicity of KL cultures, which was exacerbated by combinatorial MEK inhibition, whereas combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, <i>in vivo</i> studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of <i>in situ</i> ERBB signaling networks in conjunction with <i>ex vivo</i> drug response profiling and biochemical dissection of adaptive RTK activities may serve as a valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.</p></div>