The DOI matches its Crossref record; 49 of the 50 references it cites were found in a registry or an index.
Cell Type–specific Adaptive Signaling Responses to KRASG12C Inhibition
Open accessPublished version of a preprint
Abstract
Purpose: Covalent inhibitors of KRASG12C specifically target tumors driven by this form of mutant KRAS, yet early studies show that bypass signaling drives adaptive resistance. Although several combination strategies have been shown to improve efficacy of KRASG12C inhibitors (KRASi), underlying mechanisms and predictive strategies for patient enrichment are less clear. Experimental Design: We performed mass spectrometry–based phosphoproteomics analysis in KRASG12C cell lines after short-term treatment with ARS-1620. To understand signaling diversity and cell type–specific markers, we compared proteome and phosphoproteomes of KRASG12C cells. Gene expression patterns of KRASG12C cell lines and lung tumor tissues were examined. Results: Our analysis suggests cell type–specific perturbation to ERBB2/3 signaling compensates for repressed ERK and AKT signaling following ARS-1620 treatment in epithelial cell type, and this subtype was also more responsive to coinhibition of SHP2 and SOS1. Conversely, both high basal and feedback activation of FGFR or AXL signaling were identified in mesenchymal cells. Inhibition of FGFR signaling suppressed feedback activation of ERK and mTOR, while AXL inhibition suppressed PI3K pathway. In both cell lines and human lung cancer tissues with KRASG12C, we observed high basal ERBB2/3 associated with epithelial gene signatures, while higher basal FGFR1 and AXL were observed in cells/tumors with mesenchymal gene signatures. Conclusions: Our phosphoproteomic study identified cell type–adaptive responses to KRASi. Markers and targets associated with ERBB2/3 signaling in epithelial subtype and with FGFR1/AXL signaling in mesenchymal subtype should be considered in patient enrichment schemes with KRASi.
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“A mesenchymal-like differentiation state can act as a resistance mechanism to KRAS inhibitors [126,128,130].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [128]
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“Finally, phosphoproteomic studies on NSCLC cells treated with KRAS inhibitors identified several additional activated pathways including the upregulation of ERBB2/3 and AXL [128].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [128]
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“Phospho-proteomics analysis revealed that ERBB2/3 signaling mediates an adaptive response to KRAS G12C inhibition in epithelial cells, while feedback activation of FGFR and AXL was found in mesenchymal cells [78].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [78]
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“RTKs were also implicated in resistance to KRAS G12C inhibition associated with epithelial-mesenchymal transition (EMT) [77, 78].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [78]
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“High basal ERBB2/3 associated with epithelial gene signatures was observed in KRAS (G12C) cell lines and human lung cancers.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [131]
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“This changed cell type is more sensitive to co-inhibition by SHP2 and SOS1 [130–135].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [131]
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“The IGF1R/ERBB2/3 signaling pathway may respond to the suppressed ERK and AKT signaling after KRAS (G12C) inhibitor treatment and favor the change to epithelial cell types (Fig. 5).”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [131]
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Cites
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“The advancements in medicinal chemistry have produced high potency KRAS inhibitors (KRASi), such as ARS-1620, rapid binding to theGDP-bound inactive form, and optimizedpharmacokinetics tomaximize exposure andduration (4, 5).”
BackgroundSelective inhibition of oncogenic KRAS output with small molecules targeting the inactive state
Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1105 · Cited by 759
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Sorted by citations
KRAS Mutation: From Undruggable to Druggable in Cancer
Huang, L., Guo, Z., Wang, F., & Fu, L. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00780-4 · Cited by 1,127
Tanaka, N., Lin, J. J., Li, C., Ryan, M. B., Zhang, J., Kiedrowski, L. A., Michel, A. G., Syed, M. U., Fella, K. A., Sakhi, M., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0365 · Cited by 527
Targeting KRAS mutant cancers: from druggable therapy to drug resistance
Zhu, C., Guan, X., Zhang, X., Luan, X., Song, Z., Cheng, X., Zhang, W., & Qin, J.-J. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01629-2 · Cited by 231
The KRAS-G12C inhibitor: activity and resistance
Liu, J., Kang, R., & Tang, D. (2021) · Cancer Gene Therapy · doi:10.1038/s41417-021-00383-9 · Cited by 229
Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer
Wasko, U. N., Jiang, J., Dalton, T. C., Curiel-Garcia, A., Edwards, A. C., Wang, Y., Lee, B., Orlen, M., Tian, S., Stalnecker, C. A., et al. (2024) · Nature · doi:10.1038/s41586-024-07379-z · Cited by 209
Metadata
- Authors
- Solanki, H. S., Welsh, E. A., Fang, B., Izumi, V., Darville, L., Stone, B., Franzese, R., Chavan, S., Kinose, F., Imbody, D., Koomen, J. M., Rix, U., & Haura, E. B.
- Affiliations
- Moffitt Cancer Center (US)
- University of South Florida (US)
- Corresponding author
- Haura, Eric B.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-02-22
- Volume
- 27
- Issue
- 9
- Pages
- 2533-2548
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC9940280
- OpenAlex
- W3130115867
- Cited by
- 106
- References
- 50
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 25 · 2023: 19 · 2022: 10 · 2021: 10
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- State of Florida Bankhead Coley (5BC07)
- H. Lee Moffitt Cancer Center and Research Institute (P30-CA076292)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C, KRAS inhibitors, adaptive resistance, bypass signaling, phosphoproteomics, FGFR1, AXL, SHP2, SOS1, PI3K signaling, mTOR, lung cancer, patient enrichment, combination therapy
- MeSH terms
- Alleles, Chromatography, Liquid, Humans, Mutation, Phosphoproteins, Piperazines, Quinazolines, Biomarkers, Tumor, Signal Transduction, Proto-Oncogene Proteins p21(ras), Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Computational Biology, Amino Acid Substitution, Receptor, ErbB-3, Protein Interaction Mapping, Proteomics, Cell Line, Tumor, Receptor, Fibroblast Growth Factor, Type 1, Tandem Mass Spectrometry, Epithelial-Mesenchymal Transition, Protein Interaction Maps
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