A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution
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Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.
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Drug combinations of MEK and SRC inhibitors have been carried out in vitro using various types of cancer cell lines and to a less degree in vivo using mouse models, where enhanced anti-cancer effects have been reported.
“Notably, exploration of drug combinations of MEK and SRC inhibitors have been carried out in vitro using various types of cancer cell lines and to a less degree in vivo using mouse models, where enhanced anti-cancer effects have been reported [53–57].”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [53]
Adaptive resistance, in which the inhibited pathway is reactivated due to induction of RTKs/RTK ligand genes, is a common form of intrinsic resistance.
“Adaptive resistance (termed “rebound” by some investigators), in which the inhibited pathway is reactivated due to induction of RTKs/RTK ligand genes, is a common form of intrinsic resistance (Anderson et al., 2017; Duncan et al., 2012; Lin et al., 2015; Manchado et al., 2016; Nazarian et al., 2010; Sun et al., 2014; Zawistowski et al., 2017).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Anderson et al., 2017
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Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in InflammationPreprint
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- Authors
- Anderson, G. R., Winter, P. S., Lin, K. H., Nussbaum, D. P., Cakir, M., Stein, E. M., Soderquist, R. S., Crawford, L., Leeds, J. C., Newcomb, R., Stepp, P., Yip, C., Wardell, S. E., Tingley, J. P., Ali, M., Xu, M., Ryan, M., McCall, S. J., McRee, A. J., Counter, C. M., Der, C. J., & Wood, K. C.
- Affiliations
- Duke University (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Wood, Kris C.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 20
- Issue
- 4
- Pages
- 999-1015
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5567854
- OpenAlex
- W2736453204
- Cited by
- 80
- References
- 59
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 11 · 2022: 9 · 2021: 5 · 2020: 16 · 2019: 13 · 2018: 14
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (R01CA123031, R01CA207083, U01CA199235)
- V Foundation for Cancer Research
- Schlumberger Foundation
- School of Medicine, Duke University
- National Science Foundation (DGE-1106401, DGF-1106401)
- Duke Cancer Institute
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS-mutant cancer, combination therapy, MEK inhibitors, ERK inhibitor, PI3K inhibitors, colorectal cancer, acquired drug resistance, Src kinase inhibitor, tumor evolution, CRISPR-Cas9 screen
- MeSH terms
- Humans, Mutation, Colorectal Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Apoptosis, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats
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