KRASG12C Inhibition Remodels the Non-Small Cell Lung Cancer Surfaceome to Uncover Targetable Vulnerabilities
- 1Dana-Farber Cancer Institute
Abstract
Mutant-selective and pan-RAS(ON) multi-selective inhibitors have improved clinical outcomes for patients with RAS-driven cancers; however, adaptive resistance limits the depth and durability of response. Using an integrated genetic, transcriptomic, and mass-spectrometry-based quantitative temporal proteomic platform, we profile the adaptive response to KRASG12C inhibitors (KRASi) in KRASG12C-mutant lung adenocarcinoma models. Our analyses reveal remodeling of signaling pathways and the cell surface proteome, including cell surface proteins selectively upregulated across cell lines, tumor models, and treatment durations. Folate receptor alpha (FOLR1) emerged as a therapeutically actionable target that is significantly upregulated with KRASi and is part of a broader acute cellular state transition characterized by acquisition of an epithelial identity. Combining KRASi with mirvetuximab soravtansine-gynx, a clinically approved FOLR1-targeting antibody drug conjugate, enhanced tumor cell cytotoxicity and deepened response and tumor control in cellular and in vivo models. Additionally, this work represents a comprehensive multi-omic resource characterizing non-genetic temporal adaptation to KRASi for future mechanistic and therapeutic investigations.
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BibTeX
@misc{padhye2026krasg12c,
title = {{KRASG12C Inhibition Remodels the Non-Small Cell Lung Cancer Surfaceome to Uncover Targetable Vulnerabilities}},
author = {A. Padhye and K. Kang and F. Y. Kong and N. Sindoni and Q. Yu and B. Jiang and W.-H. Chang and O. Coker and E. Kim and J. Dilly and M. Shin and J. A. Paulo and K. Sprouffske and S. M. Brachmann and C. A. Stalnecker and A. J. Aguirre and J. D. Mancias},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.756013},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.756013v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - KRASG12C Inhibition Remodels the Non-Small Cell Lung Cancer Surfaceome to Uncover Targetable Vulnerabilities
AU - A. Padhye
AU - K. Kang
AU - F. Y. Kong
AU - N. Sindoni
AU - Q. Yu
AU - B. Jiang
AU - W.-H. Chang
AU - O. Coker
AU - E. Kim
AU - J. Dilly
AU - M. Shin
AU - J. A. Paulo
AU - K. Sprouffske
AU - S. M. Brachmann
AU - C. A. Stalnecker
AU - A. J. Aguirre
AU - J. D. Mancias
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.756013
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.756013v1
AB - Mutant-selective and pan-RAS(ON) multi-selective inhibitors have improved clinical outcomes for patients with RAS-driven cancers; however, adaptive resistance limits the depth and durability of response. Using an integrated genetic, transcriptomic, and mass-spectrometry-based quantitative temporal proteomic platform, we profile the adaptive response to KRASG12C inhibitors (KRASi) in KRASG12C-mutant lung adenocarcinoma models. Our analyses reveal remodeling of signaling pathways and the cell surface proteome, including cell surface proteins selectively upregulated across cell lines, tumor models, and treatment durations. Folate receptor alpha (FOLR1) emerged as a therapeutically actionable target that is significantly upregulated with KRASi and is part of a broader acute cellular state transition characterized by acquisition of an epithelial identity. Combining KRASi with mirvetuximab soravtansine-gynx, a clinically approved FOLR1-targeting antibody drug conjugate, enhanced tumor cell cytotoxicity and deepened response and tumor control in cellular and in vivo models. Additionally, this work represents a comprehensive multi-omic resource characterizing non-genetic temporal adaptation to KRASi for future mechanistic and therapeutic investigations.
ER -