Data from Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in <i>KRAS</i>-Mutant Cancers

Abstract

<div>Abstract<p>It is increasingly appreciated that drug response to different cancers driven by the same oncogene is different and may relate to differences in rewiring of signal transduction. We aimed to study differences in dynamic signaling changes within mutant <i>KRAS</i> (<i>KRAS</i><sup>MT</sup>), non–small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC) cells. We used an antibody-based phosphoproteomic platform to study changes in 50 phosphoproteins caused by seven targeted anticancer drugs in a panel of 30 <i>KRAS</i><sup>MT</sup> cell lines and cancer cells isolated from 10 patients with <i>KRAS</i><sup>MT</sup> cancers. We report for the first time significant differences in dynamic signaling between colorectal cancer and NSCLC cell lines exposed to clinically relevant equimolar concentrations of the pan-PI3K inhibitor pictilisib including a lack of reduction of p-AKTser473 in colorectal cancer cell lines (<i>P</i> = 0.037) and lack of compensatory increase in p-MEK in NSCLC cell lines (<i>P</i> = 0.036). Differences in rewiring of signal transduction between tumor types driven by <i>KRAS</i><sup>MT</sup> cancers exist and influence response to combination therapy using targeted agents.</p></div>