KRAS inhibition drives adaptive surfaceome remodeling and reveals ALPP/ALPPL2 as a targetable vulnerability in pancreatic cancer
- 1Dana-Farber Cancer Institute
Abstract
KRAS is mutated in over 90% of pancreatic ductal adenocarcinoma (PDAC) and is required for tumor initiation and maintenance. While clinical trials testing mutant-selective and pan-RAS inhibitors (KRASi) have demonstrated significant clinical benefit, genetic and non-genetic mechanisms of resistance limit the long-term efficacy of monotherapy strategies. Here, we used quantitative temporal analysis of the global, phosphorylation, and surface proteome to comprehensively identify non-genetic adaptive pathways and cell surface biomarkers in response to acute and long-term KRAS inhibition in PDAC. Through integrative machine learning analysis of the KRASi-proteome and publicly available datasets, we discovered top priority cell surface targets for combination therapy with KRASi. We identified Placental Alkaline Phosphatase (ALPP) as upregulated in response to KRASi through compensatory JAK2/STAT3 signaling. We developed a novel clinical grade ALPP/ALPPL2 (ALPG)-targeting antibody drug conjugate (ADC) with site-specific MMAE conjugation and demonstrated single agent efficacy in PDAC models, as well as enhanced internalization and anti-tumor efficacy in combination with KRASi. Together, these studies comprehensively define the KRASi-induced proteome and identify ALPP/ALPPL2 as a promising cell surface target for combination with KRASi to enhance response and forestall KRASi resistance.
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BibTeX
@misc{deliberty2026kras,
title = {{KRAS inhibition drives adaptive surfaceome remodeling and reveals ALPP/ALPPL2 as a targetable vulnerability in pancreatic cancer}},
author = {J. M. DeLiberty and F. Y. Kong and Q. Yu and N. Sindoni and J. Lin and K. Kang and E. Y. Kim and S. Chen and A. Padhye and O. Coker and J. H. Choe and J. A. Paulo and M. Shin and L. Hendrianto and K. Takahashi and J. Varga-Wiles and B. D. Parent and Z. Li and S. Shubitidze and T. E. Oni and D. H. Peng and T. P. Heffernan and S. Liu and B. K. S. Yeung and B. Zou and C. A. Stalnecker and A. J. Aguirre and J. D. Mancias},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.756025},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.756025v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - KRAS inhibition drives adaptive surfaceome remodeling and reveals ALPP/ALPPL2 as a targetable vulnerability in pancreatic cancer
AU - J. M. DeLiberty
AU - F. Y. Kong
AU - Q. Yu
AU - N. Sindoni
AU - J. Lin
AU - K. Kang
AU - E. Y. Kim
AU - S. Chen
AU - A. Padhye
AU - O. Coker
AU - J. H. Choe
AU - J. A. Paulo
AU - M. Shin
AU - L. Hendrianto
AU - K. Takahashi
AU - J. Varga-Wiles
AU - B. D. Parent
AU - Z. Li
AU - S. Shubitidze
AU - T. E. Oni
AU - D. H. Peng
AU - T. P. Heffernan
AU - S. Liu
AU - B. K. S. Yeung
AU - B. Zou
AU - C. A. Stalnecker
AU - A. J. Aguirre
AU - J. D. Mancias
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.756025
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.756025v1
AB - KRAS is mutated in over 90% of pancreatic ductal adenocarcinoma (PDAC) and is required for tumor initiation and maintenance. While clinical trials testing mutant-selective and pan-RAS inhibitors (KRASi) have demonstrated significant clinical benefit, genetic and non-genetic mechanisms of resistance limit the long-term efficacy of monotherapy strategies. Here, we used quantitative temporal analysis of the global, phosphorylation, and surface proteome to comprehensively identify non-genetic adaptive pathways and cell surface biomarkers in response to acute and long-term KRAS inhibition in PDAC. Through integrative machine learning analysis of the KRASi-proteome and publicly available datasets, we discovered top priority cell surface targets for combination therapy with KRASi. We identified Placental Alkaline Phosphatase (ALPP) as upregulated in response to KRASi through compensatory JAK2/STAT3 signaling. We developed a novel clinical grade ALPP/ALPPL2 (ALPG)-targeting antibody drug conjugate (ADC) with site-specific MMAE conjugation and demonstrated single agent efficacy in PDAC models, as well as enhanced internalization and anti-tumor efficacy in combination with KRASi. Together, these studies comprehensively define the KRASi-induced proteome and identify ALPP/ALPPL2 as a promising cell surface target for combination with KRASi to enhance response and forestall KRASi resistance.
ER -