Data from Genetic Events That Limit the Efficacy of MEK and RTK Inhibitor Therapies in a Mouse Model of KRAS-Driven Pancreatic Cancer

• DOI: 10.1158/0008-5472.c.6507350
• Publication Date: 2023-03-31T02:08:49Z
• Authors: Piergiorgio Petta...; Andrea Viale; Parantu Shah; Alessandro Carugo; Haoqiang Ying; Huamin Wang; Giannicola Genovese; Sahil Seth; Rosalba Minelli; Tessa Green; Emmet Huang-Hobbs; Denise Corti; Nora Sanchez; Luigi Nezi; Matteo Marchesini; Avnish Kapoor; Wantong Yao; Maria E. Di Franc...; Alessia Petrocchi; Angela K. Deem; Kenneth Scott; Simona Colla; Gordon B. Mills; Jason B. Fleming; Timothy P. Heffernan; Philip Jones; Carlo Toniatti; Ronald A. DePinho; Giulio F. Draetta
• Keywords: Selumetinib

<div>Abstract<p>Mutated KRAS (KRAS*) is a fundamental driver in the majority of pancreatic ductal adenocarcinomas (PDAC). Using an inducible mouse model KRAS*-driven PDAC, we compared KRAS* genetic extinction with pharmacologic inhibition MEK1 tumor spheres and <i>in vivo</i>. ablation blocked proliferation induced apoptosis, whereas exerted cytostatic effects. Proteomic analysis evidenced that was accompanied by sustained activation PI3K–AKT–MTOR pathway AXL, PDGFRa, HER1–2 receptor tyrosine kinases (RTK) expressed large proportion human PDAC samples analyzed. Although single each RTK alone or plus inhibitors ineffective, combination targeting all three coactivated RTKs needed to inhibit induce apoptosis both low-passage cultures. Importantly, constitutive AKT activation, which may mimic fraction AKT2-amplified able bypass induction caused ablation, highlighting potential inherent resistance mechanism inform clinical application MEK inhibitor therapy. This study suggests combinatorial-targeted therapies for cancer must be informed state putative given treatment context. In addition, our work offer explanative predictive power understanding why EGFR signaling fail how drug mechanisms arise strategies directly target KRAS. <i>Cancer Res; 75(6); 1091–101. ©2015 AACR</i>.</p></div>