Abstract A041: KRAS inhibition drives adaptive surfaceome remodeling and reveals ALPP/ALPPL2 as a targetable vulnerability in pancreatic cancer
Abstract
KRAS is the dominant oncogene in pancreatic ductal adenocarcinoma (PDAC), mutated in ∼90% of tumors, and required for tumor initiation and tumor maintenance. The overall 5-year survival rate of PDAC remains a dismal ∼10%, underscoring an unmet need to develop novel therapies to ultimately improve patients’ outcomes. While recent mutant allele-specific (KRASi) and pan-RAS inhibitors (RASi) demonstrate unprecedented activity in PDAC patients in clinical trials, genetic and non-genetic mechanisms of intrinsic and treatment-induced resistance limit the long-term efficacy of single-agent RAS/KRASi strategies. We performed quantitative temporal KRASi global, phosphoproteome, and surfaceome proteomics to comprehensively identify non-genetic adaptive pathways and cell surface biomarkers in response to acute and long-term KRAS inhibition in in vitro and in vivo models of PDAC. Global proteomics demonstrated acute suppression of KRAS-dependent proliferative and hallmark MYC and cell-cycle programs that rebounded by 7 days despite continued treatment. Resistant cells underwent large-scale proteomic reprogramming, marked by heterogeneous pathway enrichment and a consistent enrichment of lysosomal biogenesis pathways. Phosphoproteomics and kinase-substrate network analysis identified compensatory activation of RHO GTPase-associated kinases, Aurora kinase B, and PAK family kinases as adaptive responses to KRAS inhibition. Surfaceome profiling captured over 700 dysregulated cell surface proteins across timepoints, including known clinical targets such as TACSTD2, MUC1, and SLC44A4, and integration with global proteomics yielded over 1,000 quantified unique surface peptides. Integrating our KRASi-proteome with publicly available datasets, we developed and applied a machine learning algorithm to nominate and rank cell surface targets for combination targeting with KRASi. Among top-scoring hits, Placental Alkaline Phosphatase (ALPP) was validated as upregulated in response to KRASi, with ALPP upregulation mediated by KRASi-induced transcriptional compensatory JAK2/STAT3 signaling, leading to increased surface expression. Axcynsis has developed a novel clinic-ready ALPP/ALPPL2 (ALPG)-targeting antibody-drug conjugate (ADC) with a homogeneous drug-to-antibody ratio (DAR 4) and site-specific MMAE conjugation. This ADC demonstrated single-agent efficacy in in vitro and PDX models of PDAC. When this ADC was combined with KRASi, we observed enhanced internalization in multiple cancer cell lines, synergistic combination efficacy in patient-derived organoids, and anti-tumor efficacy in cell-derived xenografts of PDAC in vivo. Together, these studies establish a comprehensive proteomic resource for the PDAC/KRASi research community and identify ALPP/ALPPL2 as a promising cell surface target for combination with KRASi to drive deeper, sustained responses and prevent or forestall KRASi resistance. Jonathan M. DeLiberty, Fan Yi Kong, Qijia Yu, Nicole Sindoni, Johnson Lin, Kalisa Kang, Elizabeth Y. Kim, Sabrina Chen, Aparna Padhye, Oluwadara Coker, Joshua H. Choe, Joao A. Paulo, Myungsun Shin, Lewis Hendrianto, Kazuki Takahashi, Salome Shubitidze, Tobiloba E. Oni, Shaojun Liu, Bryan K. S. Yeung, Bin Zou, Clint A. Stalnecker, Andrew J. Aguirre, Joseph D. Mancias. KRAS inhibition drives adaptive surfaceome remodeling and reveals ALPP/ALPPL2 as a targetable vulnerability in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A041.