Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS -Mutant Lung Cancer
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Abstract
KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo. These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors. Significance: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non–small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754–69. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 681
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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 [14]
The Results and Discussion report that MEK inhibition triggers feedback activation of ERBB3 or FGFR1 signaling in different subsets of KRAS-mutant lung cancer, reactivating MAPK/ERK signaling and contributing to resistance. The claim extends this finding to KRAS-mutant cancers generally and names EGFR as a route; this paper’s EGFR feedback example concerns BRAF-inhibited colorectal cancer, not MEK-inhibited KRAS-mutant cancer. The paper primarily demonstrates reactivation of downstream MAPK/ERK signaling rather than RAS signaling itself. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEpithelial cells activate IGF-1R and ERBB3 via c-MYC, whereas mesenchymal phenotype cells activate FRS2 via SPRY4.
“Epithelial cells activate IGF-1R and ERBB3 via c-MYC, whereas mesenchymal phenotype cells activate FRS2 via SPRY4 [37, 38].”
From Epithelial-mesenchymal transition status is a remarkable biomarker for the combination treatment with avutometinib and defactinib in KRAS-mutated non-small cell lung cancer (2024) · cites this paper as [37]
The Discussion (page not provided) reports ERBB3-mediated signaling in epithelial-like KRAS-mutant lung cancer cells after MEK inhibition and describes c-MYC degradation as a way to relieve ERBB3 repression. The Results and Discussion (pages not provided) show that, in mesenchymal-like cells, MEK inhibition suppresses SPRY4 and thereby permits FGFR1-dependent FRS2 phosphorylation. The paper does not support the claimed IGF-1R activation, and the sentence omits the MEK-inhibition and KRAS-mutant lung cancer conditions. (LLM, conf=0.87)
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 [14]
Although RTKs are activated as a physiological negative feedback loop upon treatment with MEK inhibitors in KRAS-mutated NSCLC cells, the feedback loop is caused by different bypass signals in epithelial and mesenchymal phenotypes.
“Several reports have demonstrated that, although RTKs are activated as a physiological negative feedback loop upon treatment with MEK inhibitors in KRAS-mutated NSCLC cells, the feedback loop is caused by different bypass signals in the epithelial and mesenchymal phenotypes.”
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 [31]
Strategies that reverse EMT and co-target FGFR and IGFR signaling could re-sensitize EMT-induced cells to KRAS and MEK inhibitors.
“Strategies that reverse the EMT transcriptional program, as well as co-targeting FGFR and IGFR signaling in EMT-induced cells could re-sensitize them towards KRAS and MEK inhibitors (46, 47)”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [47]
High basal ERBB2/3 associated with epithelial gene signatures was observed in KRAS (G12C) cell lines and human lung cancers.
“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 [130]
This changed cell type is more sensitive to co-inhibition by SHP2 and SOS1.
“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 [130]
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.
“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 [130]
In mesenchymal-like KRAS-mutant cancer cells, reactivation of MEK and AKT was dominantly driven by FGFR1.
“In mesenchymal-like KRAS-mutant cancer cells, reactivation of MEK and AKT was dominantly driven by FGFR1.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [26]
KRAS-mutant cancer cells differing in EMT status vary in their responses to MEK inhibitors.
“KRAS-mutant cancer cells differing in EMT status vary in their responses to MEK inhibitors (26)”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [26]
In epithelial-like cancer cells, ERBB3 is preferentially activated by feedback signaling, which reactivates MEK and AKT signaling.
“In epithelial-like cancer cells, ERBB3 is preferentially activated by feedback signaling, which reactivates MEK and AKT signaling.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [26]
MEK inhibition represses the negative regulation of SPRY4.
“MEK inhibition represses the negative regulation of SPRY4.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [26]
Adaptive reactivation of MAPK signaling in the presence of a MEK inhibitor is mediated by loss of MAPK-dependent negative feedback loops and consequent induction of RTK signaling.
“Previous studies demonstrated that the adaptive reactivation of MAPK signaling in the presence of a MEK inhibitor was mediated by the loss of MAPK-dependent negative feedback loops and the consequent induction of RTKs signaling (26, 53).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [26]
Targeting MEK alone is frequently hampered by adaptive resistance, which is complex and context-dependent, and can involve activation of various RTKs, including ERBB family, AXL, PDGFR-α, or FGFR1.
“targeting of MEK alone is frequently hampered by adaptive resistance, which is complex and context-dependent, and can involve activation of various RTKs, including ERBB family, AXL, PDGFR-α, or FGFR1 (26, 53, 59–62).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [26]
ERBB3 activation was associated with resistance to MEK inhibition in KRAS-mutant NSCLC cells.
“Previous studies showed that ERBB3 activation was associated with resistance to MEK inhibition in KRAS-mutant NSCLC cells (26, 59).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [26]
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- Authors
- Kitai, H., Ebi, H., Tomida, S., Floros, K. V., Kotani, H., Adachi, Y., Oizumi, S., Nishimura, M., Faber, A. C., & Yano, S.
- Affiliations
- Kanazawa University (JP)
- Okayama University (JP)
- Virginia Commonwealth University (US)
- Hokkaido University (JP)
- Corresponding author
- Ebi, Hiromichi
- Yano, Seiji
- ORCID
- Venue
- Cancer Discovery
- Published
- 2016-06-30
- Volume
- 6
- Issue
- 7
- Pages
- 754-769
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4957999
- OpenAlex
- W2346079527
- Cited by
- 162
- References
- 55
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 12 · 2023: 16 · 2022: 26 · 2021: 23 · 2020: 16 · 2019: 19 · 2018: 17 · 2017: 7 · 2016: 3
- FWCI
- 13.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (K22CA175276)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- epithelial-mesenchymal transition, KRAS mutation, non-small cell lung cancer, MEK inhibition, FGFR1, HER3, Sprouty4, receptor tyrosine kinase, Akt, adaptive resistance, combination therapy, FGFR inhibitors
- MeSH terms
- Animals, Disease Models, Animal, Enzyme Activation, Humans, Lung Neoplasms, Membrane Proteins, Mutation, Nerve Tissue Proteins, Phosphorylation, Signal Transduction, Gene Expression, Cluster Analysis, Cell Death, Apoptosis, Receptors, Fibroblast Growth Factor, ras Proteins, Gene Expression Profiling, Receptor, ErbB-3, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Intracellular Signaling Peptides and Proteins, Extracellular Signal-Regulated MAP Kinases, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Mice, Receptor, Fibroblast Growth Factor, Type 1, Epithelial-Mesenchymal Transition
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