Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents
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Abstract
Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies. Experimental Design: We conducted comparative proteomic analysis of BRAFV600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models. Results: Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification. Conclusions: We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAFV600E CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients. Clin Cancer Res; 19(3); 657–67. ©2012 AACR.
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BRAF inhibitors have proven ineffective as single agents due to adaptive feedback re-activation of the MAPK and other signaling pathways.
“BRAF inhibitors have proven ineffective as single agents due to adaptive feedback re-activation of the MAPK and other signaling pathways [5–13, 38].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [10]
The Discussion (page unavailable) says BRAF inhibitors have not achieved the high response rates in BRAF-mutant colorectal cancer seen in melanoma. The Results report partial restoration of ERK signaling in resistant colorectal cancer cells and increased AKT signaling after treatment. The claim overgeneralizes this colorectal-cancer finding to BRAF inhibitors as single agents generally and attributes ineffectiveness solely to adaptive feedback, whereas the paper also identifies baseline PI3K/AKT activation as a resistance mechanism. (LLM, conf=0.87)
Experimental — accuracy not yet measuredInactivation of RAS upstream receptor tyrosine kinases such as EGFR can reduce RAS activation, making inhibition of EGFR an effective way to treat RAS-mutant tumors.
“Inactivation of RAS upstream receptor tyrosine kinases, such as EGFR family, can reduce RAS activation, making inhibition of EGFR an effective way to treat RAS-mutant tumors.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [616]
MAPK and PI3K are effector pathways that can be activated by RAS, and complete suppression of the MAPK pathway can help treat RAS-mutant tumors.
“On the other hand, MAPK and PI3K are effector pathways which could be respectively activated by RAS, and complete suppression of MAPK pathway can help treat RAS-mutant tumors.616,617”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [616]
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“Several mechanisms of innate resistance to BRAF inhibitors (BRAFi) in CRC have been identi fi ed, including a rapid EGFR feedback activation [7 – 9] or MAPK-pathway re-activation through multiple mechanisms [10 – 13].”
- Authors
- Mao, M., Tian, F., Mariadason, J. M., Tsao, C. C., Lemos, R., Dayyani, F., Gopal, Y. N. V., Jiang, Z.-Q., Wistuba, I. I., Tang, X. M., Bornman, W. G., Bollag, G., Mills, G. B., Powis, G., Desai, J., Gallick, G. E., Davies, M. A., & Kopetz, S.
- Affiliations
- The Royal Melbourne Hospital (AU)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Kopetz, Scott
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2013-01-31
- Volume
- 19
- Issue
- 3
- Pages
- 657-667
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3563727
- OpenAlex
- W2141172646
- Cited by
- 290
- References
- 52
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 14 · 2023: 25 · 2022: 12 · 2021: 18 · 2020: 22 · 2019: 24 · 2018: 22 · 2017: 22 · 2016: 25 · 2015: 30 · 2014: 39 · 2013: 22 · 2012: 1
- FWCI
- 14.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (KL2TR000370)
- National Cancer Institute (CA-16672, P50CA098258, K23CA136980, CA136980, R01CA172670, CA172670, P01CA130821, P50CA095060, K07CA134831, P30CA016672)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- BRAF V600E mutation, colon cancer, vemurafenib, PLX4720, PI3K/Akt signaling, PI3K inhibition, AKT inhibition, DNA methylation, hypomethylating agents, methyltransferase inhibition, acquired drug resistance, PTEN, PIK3CA, EGFR amplification, KRAS amplification, combination therapy, melanoma
- MeSH terms
- Vemurafenib, Phosphoinositide-3 Kinase Inhibitors, Animals, Antineoplastic Agents, Azacitidine, Colonic Neoplasms, Disease Models, Animal, Humans, Indoles, Methylation, Mutation, Sulfonamides, Signal Transduction, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Proliferation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice
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