A combinatorial strategy for treating KRAS-mutant lung cancer
Open accessAbstract
Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signalling rebound and adaptive drug resistance. As a consequence, genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell death in vitro and in vivo. This compensatory response shows distinct specificities: it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patients’ tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer.
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MEK inhibitor treatment in KRAS mutant cancers leads to adaptive feedback activation of RAS signaling, often through EGFR/HER family members or FGFR, limiting efficacy.
“in KRAS mutant cancers, MEK inhibitor treatment leads to adaptive feedback activation of RAS signaling, often through EGFR or other human epidermal growth factor receptor (HER) family members or FGFR, limiting efficacy (13,14).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [13]
The “FGFR1 mediates adaptive drug resistance” section reports that trametinib increased FGFR1 signaling and RAS-GTP in KRAS-mutant lung cancer cells, supporting feedback activation that limits treatment efficacy. But the “FGFR1 inhibition enhances trametinib effects” section reports no increase in EGFR in the tested cells and only limited combinatorial activity for an EGFR/ERBB2 inhibitor. The paper therefore does not support the claim that EGFR or other HER family members are often the route of this response across KRAS-mutant cancers. Page numbers are not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHER family and FGFR signaling are key mediators of adaptive feedback to RAS-MAPK pathway inhibitors.
“This finding is consistent with prior studies identifying HER family and FGFR signaling as key mediators of adaptive feedback to RAS-MAPK pathway inhibitors (10–14,21,22) and recent functional genomic screens(40).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [13]
The Discussion identifies FGFR1 feedback activation as a prominent mechanism of resistance to the MEK inhibitor trametinib in KRAS-mutant lung cancer. The “FGFR1 inhibition enhances trametinib effects” section reports some combinatorial activity for an EGFR/ERBB2 inhibitor, but does not establish HER-family signaling as a key mediator in this setting. The claim also generalizes beyond the specific inhibitor and cancer contexts examined. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAdaptive feedback activation of various RTKs is ubiquitously involved in mediating resistance to targeted therapy.
“Adaptive feedback activation of various RTKs is ubiquitously involved in mediating resistance to targeted therapy.”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [70]
The ‘FGFR1 mediates adaptive drug resistance’ section says several RTKs have been implicated in resistance to RAS-pathway antagonists. But the Discussion identifies FGFR1—not the other RTKs tested—as the relevant mechanism in this study, and reports that the response varies by tumor type. The paper therefore supports RTK-mediated adaptive resistance, but not the claim that it is ubiquitous across targeted therapies. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRebound signaling of FGFR was found in KRAS-mutant NSCLC cells treated with the MEK inhibitor trametinib, leading to reactivation of RAS-mediated signaling.
“Rebound signaling of fibroblast growth factor receptor (FGFR) was found in KRAS-mutant NSCLC cells treated with the MEK inhibitor trametinib, leading to reactivation of RAS-mediated signaling [70].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [70]
The feedback activations of redundant signaling mediated by RTKs confer MEKi resistance.
“The feedback activations of redundant signaling mediated by RTKs were considered to confer MEKi resistance in previous studies [17, 28, 31, 32].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [32]
MEK-I treatment of KRAS-mutant tumors fails, at least in part due to induction of genes encoding multiple RTKs and/or their ligands, which differ between tumors even of a single histotype.
“MEK-I treatment of KRAS-mutant tumors fails, at least in part due to induction of genes encoding multiple RTKs and/or their ligands, which differ between tumors even of a single histotype (Hymowitz and Malek, 2018; Manchado et al., 2016; Ryan and Corcoran, 2018; Sun et al., 2014).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Manchado et al., 2016
An independent shRNA screen study had similar findings in KRAS-mutant lung and pancreatic cancer cells.
“another independent study using short hairpin (sh) RNA screen had similar findings in KRAS-mutant lung and pancreatic cancer cells (27).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [27]
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ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism
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Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition
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- Authors
- Manchado, E., Weissmueller, S., Morris, J. P., Chen, C.-C., Wullenkord, R., Lujambio, A., de Stanchina, E., Poirier, J. T., Gainor, J. F., Corcoran, R. B., Engelman, J. A., Rudin, C. M., Rosen, N., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Corresponding author
- Rosen, Neal
- Lowe, Scott W.
- ORCID
- Venue
- Nature
- Published
- 2016-06-22
- Volume
- 534
- Issue
- 7609
- Pages
- 647-651
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4939262
- OpenAlex
- W2474854223
- Semantic Scholar
- 3e2a1baba22310a9cc05860c7898e9d973623c8f
- Cited by
- 403
- References
- 36
- Citations by year
- 2026: 18 · 2025: 24 · 2024: 23 · 2023: 35 · 2022: 48 · 2021: 47 · 2020: 49 · 2019: 50 · 2018: 51 · 2017: 43 · 2016: 15
- FWCI
- 47.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (P50CA127003, R01CA169351, P01CA129243, P30CA008748)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- 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
- Keywords
- KRAS-mutant lung adenocarcinoma, trametinib, MEK inhibition, FGFR1, adaptive drug resistance, MAPK signaling, combination therapy, ponatinib, pancreatic cancer
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Animals, Antineoplastic Combined Chemotherapy Protocols, Colonic Neoplasms, Disease Models, Animal, Drug Screening Assays, Antitumor, Enzyme Activation, Female, Humans, Imidazoles, Lung Neoplasms, Mutation, Pancreatic Neoplasms, Phosphorylation, Pyridazines, Pyridones, Pyrimidinones, Proto-Oncogene Proteins p21(ras), Cell Death, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Feedback, Physiological, Cell Proliferation, Mutant Proteins, Mice, Receptor, Fibroblast Growth Factor, Type 1
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