Abstract C024: Quantitative mass spectrometry-based multi-omic profiling to overcome drug resistance in pancreatic cancer post KRAS G12D inhibition

Abstract Recently developed inhibitors targeting the KRASG12D oncoprotein are undergoing clinical trial evaluation including in patients with pancreatic adenocarcinoma (PDAC). However, resistance to such targeted therapies is a frequent occurrence, potentially undermining the long-term success of KRAS inhibitors (KRASi). To uncover the adaptive pathways and cell surface biomarkers to KRASi and to identify effective drug combinations that can overcome resistance, we employ a mass spectrometry-based quantitative temporal proteomics workflow. This approach allows us to map the proteomic changes in response to KRASi in both in vitro and in vivo PDAC models. We identify and quantify 10, 898 proteins, creating the most extensive proteomic dataset related to KRASi to date. We identify shared mechanisms of both acute and long-term adaptation to KRASi across PDAC models. Utilizing this proteomic information, we are pinpointing drug combinations that pair KRASi with inhibitors of CDK4/6, AURKA, and mTOR to increase cytotoxicity and thereby reduce development of long-term resistance. Surfaceome analyses identifies cell surface proteins upregulated upon acute and long-term KRASi, including TACSTD2 (Trop-2). Antibody-drug conjugates targeting upregulated surface proteins may be a useful orthogonal approach towards preventing or circumventing KRASi resistance with testing of Trop-2 and other candidates ongoing. In summary, through mass spectrometry-based quantitative temporal proteomics, we identify proteomic adaptations to KRASi in PDAC and propose combination treatments with promising therapeutic potential. Citation Format: Qijia Yu, Nicole Sindoni, Huan Zhang, Ziyue Li, Joao A. Paulo, Andrew J. Aguirre, Joseph D. Mancias. Quantitative mass spectrometry-based multi-omic profiling to overcome drug resistance in pancreatic cancer post KRAS G12D inhibition abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr C024.