Wnt/β-Catenin Pathway Activation Mediates Adaptive Resistance to BRAF Inhibition in Colorectal Cancer
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Abstract
One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer. Although many studies on BRAF inhibitor resistance in colorectal cancer have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on colorectal cancer resistance to BRAF inhibition. We found that treatment with BRAF inhibitors (both current and next-generation BRAF inhibitors) upregulated the Wnt/β-catenin pathway in BRAFV600E-mutant colorectal cancer cell lines through activating the cytoplasmic tyrosine kinase focal adhesion kinase (FAK). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR or ERK1/2 activation, implying that BRAF inhibitor treatment-induced hyperactivation of Wnt signaling is “pathway reactivation”-independent. BRAF inhibition–induced Wnt pathway activation was further validated in preclinical models of BRAFV600E-mutant colorectal cancer, including cell line xenograft model and a patient-derived xenograft model. Combined inhibition of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture model and mouse xenograft model. Overall, the current study has identified activation of the Wnt/β-catenin pathway as a novel fundamental cause of colon cancer resistance to BRAF inhibition. Our results suggest that although complete vertical pathway blockade is pivotal for effective and durable control of BRAF-mutant colorectal cancer, cotargeting parallel adaptive signaling—the Wnt/β-catenin pathway—is also essential. Mol Cancer Ther; 17(4); 806–13. ©2017 AACR.
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RAS/RAF-mutated CRC targeted therapies have been largely ineffective, likely due to complex resistance mechanisms such as intrinsic and adaptive resistance.
“Although RAS/RAF-mutated CRC has been targeted for the development of therapeutic inhibitors, they have been largely ineffective, likely due to complex resistance mechanisms such as intrinsic and adaptive resistance [5–12].”
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 [12]
The Introduction reports that BRAF-mutant CRC does not benefit from BRAF inhibitor treatment and links de novo and acquired resistance to adaptive pathway reactivation. The Abstract also identifies Wnt/β-catenin activation as an adaptive resistance mechanism. These passages support the claim for BRAF-mutant CRC, but do not establish it for RAS-mutant CRC generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAdaptive resistance can rapidly induce drug resistance to targeted therapy in tumors that are natively sensitive.
“Thus, AR can rapidly induce drug resistance to targeted therapy in tumors that are natively “sensitive”.”
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 [12]
The Abstract and Introduction describe adaptive signaling that contributes to resistance to BRAF inhibition in colorectal cancer. But they say BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer, rather than studying tumors natively sensitive to it. The cited passages also do not establish how rapidly resistance develops. (LLM, conf=0.84)
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References 28 · Cited by 104
- Authors
- Chen, G., Gao, C., Gao, X., Zhang, D. H., Kuan, S.-F., Burns, T. F., & Hu, J.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Hu, Jing
- Venue
- Molecular Cancer Therapeutics
- Published
- 2018-04-01
- Volume
- 17
- Issue
- 4
- Pages
- 806-813
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC5882543
- OpenAlex
- W2768887441
- Cited by
- 104
- References
- 28
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 16 · 2023: 8 · 2022: 13 · 2021: 15 · 2020: 17 · 2019: 8 · 2018: 7
- FWCI
- 3.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- USPHS (CA166197 and CA175202)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- Wnt/β-catenin signaling, BRAF inhibitor resistance, BRAF V600E mutation, colorectal cancer, focal adhesion kinase, adaptive resistance, combination therapy, patient-derived xenografts
- MeSH terms
- Animals, Humans, Male, Mice, Nude, Mutation, Tumor Cells, Cultured, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Apoptosis, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Cell Proliferation, Wnt1 Protein, beta Catenin, Mice
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