We have previously identified two tumor specific molecular subtypes in pancreatic ductal adenocarcinoma (PDAC), basal-like and classical. Although basal-like tumors are found in less than 20% of patients, patients with basal-like tumors have a worse prognosis and are largely resistant to FOLFIRINOX chemotherapy. To identify targetable basal-like subtype specific vulnerabilities in PDAC, we utilized Multiplexed kinase Inhibitor Beads and Mass Spectrometry (MIB-MS) to profile the kinome in patient derived xenograft (PDX) models that recapitulate the tumor subtypes found in patients. MIB-MS results show that kinase expression is significantly associated with molecular subtype. Notably, basal-like tumors show increased expression of receptor tyrosine kinases (RTKs) including EGFR, MET, and IGF1R and MAP kinase members MEK2 and BRAF indicating activation of the MAP kinase signaling cascade. These RTKs including EGFR are also differentially expressed in primary patient tumors suggesting the true efficacy of EGFR and other kinase inhibitors in basal-like tumors may have been masked by the larger proportion of patients (>80%) with unresponsive classical tumors. Furthermore, inhibition of MAP kinase signaling with the MEK inhibitor trametinib results in kinome reprogramming exclusive to classical tumors. MIB-MS profiling reveals upregulation of TAOK3 and MEK3/6 indicating activation of p38 MAP kinase signaling as a classical subtype specific compensatory mechanism against MEK inhibition. Overall, these results present actionable basal-like subtype specific kinase targets by defining a novel subtype specific kinome in PDAC. Precision approaches in clinical trials are needed to determine if new and previously thought to be disappointing kinase inhibitors may be efficacious in patients with basal-like tumors.

Citation Format: Yi Xu, Ashley B. Morrison, Silvia G. Herrera, Michael P. East, Gary L. Johnson, Jen Jen Yeh. Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR011.