EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF -Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib
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Abstract
BRAF mutations occur in 10% to 15% of colorectal cancers and confer adverse outcome in the metastatic setting. Although RAF inhibitors such as vemurafenib (PLX4032) have proven effective in the treatment of BRAF-mutant melanoma, they are surprisingly ineffective in BRAF-mutant colorectal cancers, and the reason for this disparity remains unclear. Compared with BRAF-mutant melanoma cells, BRAF-mutant colorectal cancer cells were less sensitive to vemurafenib, and phospho-extracellular signal-regulated kinase (P-ERK) suppression was not sustained in response to treatment. Although transient inhibition of P-ERK by vemurafenib was observed in colorectal cancer, rapid ERK reactivation occurred through epidermal growth factor receptor (EGFR)-mediated activation of RAS and CRAF. BRAF-mutant colorectal cancers expressed greater levels of phospho-EGFR than BRAF-mutant melanomas, suggesting that colorectal cancers are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of mitogen-activated protein kinase (MAPK) signaling in BRAF-mutant colorectal cancer cells and markedly improved efficacy in vitro and in vivo. These findings support the evaluation of combined RAF and EGFR inhibition in patients with BRAF-mutant colorectal cancer. Significance: BRAF valine 600 (V600) mutations occur in 10% to 15% of colorectal cancers, yet these tumors show a surprisingly low clinical response rate (∼5%) to selective RAF inhibitors such as vemurafenib, which have produced dramatic response rates (60%–80%) in melanomas harboring the identical BRAF V600 mutation. We found that EGFR-mediated MAPK pathway reactivation leads to resistance to vemurafenib in BRAF-mutant colorectal cancers and that combined RAF and EGFR inhibition can lead to sustained MAPK pathway suppression and improved efficacy in vitro and in tumor xenografts. Cancer Discovery; 2(3); 227–35. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 193
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BRAFi (PLX4032 or vemurafenib) induces rapid feedback activation of EGFR in BRAF V600E-mutated CRC cell lines, supporting continued proliferation in the presence of BRAF inhibition.
“For example, BRAFi (PLX4032 or vermurafenib) induces a rapid, marked feedback activation of EGFR in the BRAF (V600E)-mutated CRC cell lines, supporting continued proliferation in the presence of BRAF inhibition [9, 11].”
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 [11]
The Results and Discussion explicitly say that vemurafenib did not increase EGFR activation: phospho-EGFR did not rise from 0 to 48 hours. The paper instead reports rapid reactivation of downstream MAPK signaling mediated by EGFR that was already active before treatment. Thus it supports the resistance mechanism, but contradicts the claim that treatment rapidly activates EGFR itself. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredBRAF inhibition in BRAFV600 mutant cancers causes RTK-mediated reactivation of MAPK signaling through wild type RAS and RAF, particularly in colorectal cancer.
“BRAF inhibition in BRAFV600 mutant cancers leads to loss of negative feedback signals regulated by the MAPK pathway, leading to receptor tyrosine kinase (RTK)-mediated reactivation of MAPK signaling through wild type RAS and RAF, particularly in specific tumor types, such as colorectal cancer (9–12).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [11]
The Results and Discussion (page unavailable) support EGFR-mediated reactivation of RAS, CRAF and MAPK signaling after vemurafenib treatment in BRAF-mutant colorectal cancer. The citing sentence also presents loss of MAPK-regulated negative feedback as the cause; the Discussion offers that mechanism as a possibility and says further study is needed to establish it. The paper does not explicitly establish that the RAS and RAF involved are wild type. (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 [11]
The Results (page not provided) identify EGFR, a HER-family receptor, as the predominant mediator of MAPK reactivation after RAF inhibition in BRAF-mutant colorectal cancer cells. The Discussion (page not provided) describes a possible feedback mechanism but says it remains unproven. Our copy does not establish FGFR signaling as a mediator, so it supports only the EGFR portion of the broader claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAdaptive feedback resistance has been a key limitation in prior clinical efforts to target the RAS-MAPK pathway.
“However, adaptive feedback resistance has been a key limitation in prior clinical efforts to target the RAS-MAPK pathway.”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [11]
The Discussion (page unavailable) links the poor response of BRAF-mutant colorectal cancers to vemurafenib with EGFR-mediated reactivation of MAPK signaling, supporting feedback resistance as a limitation in that setting. The paper does not establish that it was a key limitation across prior clinical efforts to target the RAS–MAPK pathway more broadly; its mechanistic evidence comes from cell and xenograft studies. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRTK-driven feedback reactivation of RAS-MAPK signaling has been identified as a key driver of resistance in BRAFV600E cancers treated with BRAF inhibitors (colorectal cancer in particular) and in KRAS-mutant cancers treated with MEK inhibitors.
“For example, RTK-driven feedback reactivation of RAS-MAPK signaling has been identified as a key driver of resistance in BRAFV600E cancers treated with BRAF inhibitors (colorectal cancer in particular) and in KRAS-mutant cancers treated with MEK inhibitors (11,12,32).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [11]
The Results and Discussion (page not provided) identify EGFR-driven RAS–MAPK reactivation as a mechanism of reduced sensitivity to vemurafenib in BRAF-mutant colorectal cancer. Our copy does not support the separate claim about RTK-driven resistance to MEK inhibitors in KRAS-mutant cancers. (LLM, conf=0.88)
Experimental — accuracy not yet measured
The 13-gene signature was developed from cell lines treated with MEKi for 72 h, during which adaptive resistance could be induced.
“It is noteworthy that the 13-gene signature was developed from cell lines treated with the MEKi for a 72 h period [6] during which AR could be induced [11].”
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 [11]
Citation [11] is attached to the claim that adaptive resistance could arise during the 72-hour treatment period, not to the development of the 13-gene signature. The Results and Discussion (pages unavailable) report MAPK reactivation as early as 3–6 hours after treatment with the RAF inhibitor vemurafenib. They do not establish that this occurred during MEK-inhibitor treatment; the Results instead say a MEK inhibitor blocked the observed rebound. (LLM, conf=0.83)
Experimental — accuracy not yet measuredRAS/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 [11]
The Introduction reports a roughly 5% response rate to vemurafenib in BRAF-mutant CRC, and the Discussion attributes reduced sensitivity to EGFR-mediated reactivation of MAPK signaling. This supports ineffectiveness of RAF inhibition and a resistance mechanism in BRAF-mutant CRC, but the paper does not establish the broader claim for RAS-mutated CRC or targeted therapies generally. Page numbers are not supplied in our copy. (LLM, conf=0.87)
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 [11]
The Results report that vemurafenib initially suppressed MAPK signaling in BRAF-mutant colorectal cancer cells, but signaling rebounded within hours; the Discussion links this reactivation to reduced drug sensitivity. The paper describes these cancers as relatively insensitive to vemurafenib from the outset, not as tumors that were natively drug-sensitive and then developed resistance. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCombined EGFR and BRAF blockade proved synthetic lethality in preclinical models of BRAFV600E CRC and modestly improves survival of patients with advanced disease.
“Combined EGFR and BRAF blockade proved synthetic lethality in preclinical models of BRAFV600E CRC and modestly improves survival of patients with advanced disease [7, 8, 15–17].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [7]
The Results (page unavailable) show that combined RAF and EGFR inhibition reduced viable BRAF-mutant CRC cells and caused tumor regressions in xenografts. The paper does not establish synthetic lethality or report improved survival in patients with advanced disease; the Discussion (page unavailable) instead calls for clinical evaluation of the combination. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRapid EGFR feedback activation is one of the mechanisms of intrinsic resistance to BRAFi in BRAFV600E CRC, does not occur in BRAFV600E melanoma, and explains the sensitivity of melanoma to BRAF inhibitors in the clinic.
“Rapid EGFR feedback activation has been established as one of the mechanisms of intrinsic resistance to BRAFi in BRAFV600E CRC, which does not occur in BRAFV600E melanoma and explains the sensitivity of the latest to BRAF inhibitors in the clinic [7, 8].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [7]
The Introduction and Discussion report rapid EGFR-mediated MAPK reactivation as a mechanism of vemurafenib resistance in BRAF-mutant CRC, and link lower receptor activity in melanoma to its greater sensitivity. But the Discussion explicitly says EGFR activation itself did not increase after treatment; it was downstream signaling that reactivated. The Results also show lower EGFR phosphorylation in melanoma, not that the mechanism categorically never occurs there. (LLM, conf=0.89)
Experimental — accuracy not yet measuredBRAF 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 [7]
The Discussion reports that vemurafenib has produced strong responses in BRAF-mutant melanoma but has been ineffective in BRAF-mutant colorectal cancer, where EGFR-mediated MAPK reactivation reduces sensitivity. The Results also report PI3K–AKT activation after treatment, but do not establish it as the cause of this insensitivity. The claim overgeneralizes the colorectal-cancer finding to BRAF inhibitors as single agents and to reactivation of other pathways as a cause. (LLM, conf=0.89)
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 [68]
The Discussion (page unavailable) links EGFR-mediated MAPK reactivation to reduced sensitivity to vemurafenib in BRAF-mutant colorectal cancer. It does not support the claim that adaptive activation of various RTKs ubiquitously mediates resistance to targeted therapy: the authors found no increased EGFR activation after treatment, and the Results report that most measured RTKs were not induced. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEGFR is required for CRC progression and treatment response.
“EGFR is required for CRC progression and treatment response [28–30]”
From Feedback activation of EGFR/wild-type RAS signaling axis limits KRASG12D inhibitor efficacy in KRASG12D-mutated colorectal cancer (2023) · cites this paper as [28]
The Discussion (page not provided) reports that EGFR exerted dominant control over RAS and MAPK signaling in the paper’s BRAF-mutant CRC cell-line models, and that combined RAF/EGFR inhibition improved treatment response in those models and xenografts. It does not establish that EGFR is required for CRC progression or for treatment response across CRC generally; it also allows that some BRAF-mutant CRCs may depend on other receptors. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMEKi may mediate adaptive resistance by a mechanism independent of EGFR.
“This suggested that, in contrast to that observed with BRAFi treatments [9, 11], MEKi may mediate AR by a mechanism independent of EGFR.”
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 [11]
Development of resistance to PLX8394 did not lead to activation of the EGFR/MAPK pathways.
“However, unlike first-generation BRAF inhibitors [21,22], development of resistance to PLX8394 did not lead to activation of the EGFR/MAPK pathways (Supp. Fig. 1A).”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [21]
EGFR-mediated MAPK reactivation has been previously implicated in the insensitivity of BRAF mutant CRC to the first-generation of BRAF inhibitors.
“EGFR-mediated MAPK reactivation has been previously implicated in the insensitivity of BRAF mutant CRC to the first-generation of BRAF inhibitors [21].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [21]
EGFR activation mediates resistance of CRC to the BRAF V600E inhibitor vemurafenib through reactivation of downstream signaling.
“For example, EGFR activation mediates resistance of CRC to the BRAF V600E inhibitor vemurafenib through reactivation of downstream signaling [68, 69].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [68]
BRAF V600E CRC have limited sensitivity to single agent RAF inhibitors, and this is a result of an adaptive response selectively triggered in CRC.
“We and others previously reported that BRAF V600E CRC have limited sensitivity to single agent RAF inhibitors, and this is a result of an adaptive response selectively triggered in CRC(16-18).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [17]
The negative clinical outcome of MEK inhibition in CRC was attributed to blockade of MEK releasing negative feedback regulation of RTKs.
“The negative clinical outcome was attributed to the fact that blockading MEK released the negative feedback regulation of RTKs [15–17].”
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 [16]
Best responses of colorectal cancer cell xenografts to combined EGFR and BRAF inhibition were only disease stabilizations or mild tumor regressions.
“the best responses of CRC cell xenografts to such combinations were only disease stabilizations or mild tumor regressions [52, 58-60].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [59]
Combined inhibition of EGFR and BRAF can be synergistic in BRAF-mutant colorectal cancers.
“preclinical studies have provided a proof of principle that the combined inhibition of EGFR and BRAF can be synergistic in BRAF-mutant CRCs”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [59]
The lack of efficacy of BRAF inhibitors in BRAF-mutant colorectal cancer is ascribed to feedback activation of EGFR leading to EGFR-dependent compensatory signals.
“this lack of efficacy has been ascribed to the feedback activation of EGFR, which ensues as a consequence of BRAF inactivation and leads to EGFR-dependent compensatory signals [58, 59].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [59]
In BRAF V600E mutant cancers, BRAF inhibition can lead to rapid EGFR-mediated feedback activation.
“Multiple studies have demonstrated that in BRAF V600E mutant cancers, BRAF inhibition can lead to rapid EGFR-mediated feedback activation [95,96,104].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [96]
KRAS (G12C) inhibition induces a higher rebound of phosphorylated ERK in CRC cells than in NSCLC cells.
“KRAS (G12C) inhibition induces a higher rebound of phosphorylated ERK in CRC cells than in NSCLC cells.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [101]
Enhanced EGFR signaling is thought to mediate adaptive resistance of KRAS (G12C) inhibitors.
“Hence, enhanced EGFR signaling is thought to mediate adaptive resistance of KRAS (G12C) inhibitors [99–101].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [101]
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- Authors
- Corcoran, R. B., Ebi, H., Turke, A. B., Coffee, E. M., Nishino, M., Cogdill, A. P., Brown, R. D., Della Pelle, P., Dias-Santagata, D., Hung, K. E., Flaherty, K. T., Piris, A., Wargo, J. A., Settleman, J., Mino-Kenudson, M., & Engelman, J. A.
- Affiliations
- Tufts Medical Center (US)
- Authors' Affiliations: 1Massachusetts General Hospital Cancer Center, 2Department of Medicine, Harvard Medical School, 3Division of Gastro-enterology, Tufts Medical Center, and Departments of 4Pathology and 5Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and 6Genentech, Inc., South San Francisco, California
- Corresponding author
- Engelman, Jeffrey A.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2012-03-01
- Volume
- 2
- Issue
- 3
- Pages
- 227-235
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3308191
- OpenAlex
- W2110682589
- Semantic Scholar
- 5ef58b9e7dec3e8e77bf11999b6ae8a7bb74e258
- Cited by
- 1,022
- References
- 21
- Citations by year
- 2026: 41 · 2025: 53 · 2024: 67 · 2023: 72 · 2022: 88 · 2021: 100 · 2020: 86 · 2019: 62 · 2018: 66 · 2017: 66 · 2016: 70 · 2015: 86 · 2014: 75 · 2013: 62 · 2012: 25
- FWCI
- 39.70
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA127003, R01CA166480, U01CA141457, R01CA140594, P50CA090578, K08CA120060, R01CA137008)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Keywords
- BRAF V600 mutation, colorectal cancer, vemurafenib, RAF inhibitors, EGFR, MAPK signaling, drug resistance, Raf-1, Ras, combination therapy, BRAF-mutant melanoma
- MeSH terms
- Vemurafenib, Animals, Humans, Immunohistochemistry, Indoles, Male, Mice, Nude, Sulfonamides, Colorectal Neoplasms, HT29 Cells, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Cell Line, Tumor, raf Kinases, Proto-Oncogene Proteins B-raf, Cell Growth Processes, Mice, ErbB Receptors
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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