Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF -Mutant Thyroid Carcinomas
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Abstract
The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. In contrast to melanomas, inhibition of mitogen-activated protein kinase (MAPK) signaling by PLX4032 is transient in thyroid and colorectal cancer cells. The rebound in extracellular signal-regulated kinase (ERK) in thyroid cells is accompanied by increased HER3 signaling caused by induction of ERBB3 (HER3) transcription through decreased promoter occupancy by the transcriptional repressors C-terminal binding protein 1 and 2 and by autocrine secretion of neuregulin-1 (NRG1). The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MAP-ERK kinase inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific receptor tyrosine kinases, and the abundance of their respective ligands. Significance: Thyroid cancer cell lines with mutant BRAF are resistant to PLX4032. RAF inhibitors transiently inhibit the ERK pathway and de-repress HER3 transcription. In the context of constitutive NRG1 secretion, this results in an ERK and AKT rebound that diminishes the antitumor effects of RAF inhibitors, which is overcome by combination with lapatinib. Cancer Discov; 3(5); 520–33. ©2013 AACR. See related commentary by Girotti and Marais, p. 487 This article is highlighted in the In This Issue feature, p. 471
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HER 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 [10]
The Results and Discussion (page unavailable) identify HER2/HER3 signaling as a mediator of rebound signaling and reduced response to RAF or MEK inhibitors in BRAF-mutant thyroid cancer cells. Our copy does not identify FGFR signaling as a mediator; searches for “FGFR” and “fibroblast growth factor” found no supporting passage. The paper also emphasizes that the relevant reactivated receptors vary by cell type. (LLM, conf=0.90)
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 [10]
Experimental — accuracy not yet measuredDeterminants of primary resistance differ among tumor types that up-regulate various RTKs or ligands in response to pathway inhibition.
“Determinants of primary resistance are not the same in different tumor types that up-regulate various RTKs or their ligands in response to pathway inhibition (111-113).”
From Targeting CDK4 and CDK6: From Discovery to Therapy (2016) · cites this paper as [112]
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- Authors
- Montero-Conde, C., Ruiz-Llorente, S., Dominguez, J. M., Knauf, J. A., Viale, A., Sherman, E. J., Ryder, M., Ghossein, R. A., Rosen, N., & Fagin, J. A.
- Affiliations
- Authors' Affiliations: 1Human Oncology and Pathogenesis Program, 2Sloan Kettering Institute, Departments of 3Medicine and 4Pathology, and 5Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Fagin, James A.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2013-05-01
- Volume
- 3
- Issue
- 5
- Pages
- 520-533
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3651738
- OpenAlex
- W2141787711
- Semantic Scholar
- b419cecd557105903ef17c5ad82c80b067a6fee4
- Cited by
- 382
- References
- 41
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 14 · 2023: 29 · 2022: 30 · 2021: 29 · 2020: 30 · 2019: 20 · 2018: 40 · 2017: 22 · 2016: 31 · 2015: 47 · 2014: 43 · 2013: 22
- FWCI
- 21.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- AstraZeneca
- Memorial Sloan-Kettering Cancer Center
- Plexxikon
- National Institutes of Health (5r01ca072598-05)
- Chugai Pharmaceutical
- National Cancer Institute (CA72598, CA 50706, R01CA050706, R01CA072597, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- vemurafenib, RAF inhibitors, MEK inhibitors, product inhibition, MAPK signaling, neuregulin-1, lapatinib, Akt signaling, drug resistance, combination therapy
- MeSH terms
- Antineoplastic Agents, Humans, Neoplasms, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, ErbB Receptors
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