Abstract B057: Antibody-based drug targeting of the KRAS inhibitor-induced pancreatic cancer cell surfaceome

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the United States. KRAS is the dominant oncogene in PDAC and is mutated in ∼90% of tumors. While considered undruggable for 40 years, recent advances have led to the development of mutant allele-specific KRAS and pan-RAS inhibitors (KRASi) that demonstrate activity in PDAC patients in early clinical trials. Unfortunately, intrinsic and treatment-induced resistance have limited the long-term efficacy of single-agent KRASi therapies. Given the multitude of resistance mechanisms identified within the RAS-MAPK signaling pathway, it will be essential to identify new combination therapy strategies that target orthogonal signaling pathways or adaptive alterations in cell surface molecules to combat resistance to KRASi monotherapy. We hypothesize that combination strategies of KRAS inhibition and antibody drug conjugates (ADC) targeting cell surface proteins upregulated in response to KRAS inhibition will drive deeper therapeutic responses and prevent the development of KRAS inhibitor resistance. We employed a mass spectrometry-based quantitative temporal proteomics workflow to identify the adaptive pathways and cell surface biomarkers in response to acute and long-term KRAS inhibition in PDAC. Using this approach, we have mapped the proteomic changes in response to KRASi in both ex vivo and in vivo PDAC models. We identified and quantified 9, 951 proteins, 10, 448 phosphosites, and 1, 200 surface proteins, creating the most extensive proteomic dataset across acute adaptation and long-term resistance to oncogenic KRAS inhibition in PDAC. In global proteome experiments, we observe suppression of MYC and TEAD-associated gene signatures in acute KRAS inhibition that are reactivated at long-term resistance. Phosphoproteomic analyses revealed increased activity of the PAK family during acute KRAS inhibition, presenting a potential therapeutic opportunity for combination treatments with small molecules inhibitors to overcome KRASi resistance. Cell surfaceome analyses identified key cell surface proteins consistently upregulated upon KRAS inhibition across models. Increased expression of several targets, including TACSTD2 (Trop-2), MUC1, and ALPP, have been validated in cell and xenograft models. Evaluations using antibody-drug conjugates (ADC) targeting ALPP and MUC1 in combination with KRASi to induce anti-tumor responses in PDAC models are ongoing. Together, these studies establish a comprehensive proteomic resource for the PDAC/KRASi research community and identify targets for antibody-based combinations with early evidence of therapeutic potential. Citation Format: Fan Yi Kong, Jonathan M. Deliberty, Nicole Sindoni, Qijia Yu, Aparna Padhye, Johnson Lin, Sabrina Chen, Ziyue Li, Joshua H. Choe, Joao A. Paulo, Kazuki Takahashi, Tobiloba Oni, Andrew J. Aguirre, Clint A. Stalnecker, Joseph D. Mancias. Antibody-based drug targeting of the KRAS inhibitor-induced pancreatic cancer cell surfaceome abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B057.