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Ref Type Journal Article
PMID (33568355)
Authors Adamopoulos C, Ahmed TA, Tucker MR, Ung PMU, Xiao M, Karoulia Z, Amabile A, Wu X, Aaronson SA, Ang C, Rebecca VW, Brown BD, Schlessinger A, Herlyn M, Wang Q, Shaw DE, Poulikakos PI
Title Exploiting allosteric properties of RAF and MEK inhibitors to target therapy-resistant tumors driven by oncogenic BRAF signaling.
Journal Cancer discovery
Vol
Issue
Date 2021 Feb 10
URL
Abstract Text Current clinical RAF inhibitors (RAFi) inhibit monomeric BRAF (mBRAF), but are less potent against dimeric BRAF (dBRAF). RAFi equipotent for mBRAF and dBRAF have been developed, but are predicted to have lower therapeutic index. Here we identify a third class of RAFi that selectively inhibits dBRAF over mBRAF. Molecular Dynamic simulations reveal restriction of the movement of the BRAF αC-helix as the basis of inhibitor selectivity. Combination of inhibitors based on their conformation selectivity (mBRAF- plus dBRAF-selective plus the most potent BRAF-MEK disruptor MEK inhibitor) promoted suppression of tumor growth in BRAF(V600E) therapy-resistant models. Strikingly, the triple combination showed no toxicities, whereas dBRAF-selective plus MEK inhibitor treatment caused weight loss in mice. Finally, the triple combination achieved durable response and improved clinical wellbeing in a stage IV colorectal cancer patient. Thus, exploiting allosteric properties of RAF and MEK inhibitors enables the design of effective and well-tolerated therapies for BRAF(V600E) tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colon adenocarcinoma predicted - sensitive Dabrafenib + Regorafenib + Trametinib Case Reports/Case Series Actionable In a clinical case study, combination treatment with Stivarga (regorafenib), Tafinlar (dabrafenib), and Mekinist (trametinib) in a patient with colon adenocarcinoma harboring BRAF V600E led to stable disease, and treatment continued for eight months, at which time some disease progression was observed (PMID: 33568355). 33568355
BRAF V600E colorectal cancer sensitive Dabrafenib + RAF709 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with RAF709, Tafinlar (dabrafenib), and Mekinist (trametinib) in colorectal cancer cell lines harboring BRAF V600E resulted in suppression of colony formation in culture (PMID: 33568355). 33568355
BRAF V600E melanoma sensitive Dabrafenib + LXH 254 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with LXH 254, Tafinlar (dabrafenib), and Mekinist (trametinib) in a melanoma cell line harboring BRAF V600E resulted in suppression of colony formation in culture (PMID: 33568355). 33568355
BRAF V600E colorectal cancer sensitive Dabrafenib + Regorafenib + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, combination treatment with Stivarga (regorafenib), Tafinlar (dabrafenib), and Mekinist (trametinib) in colorectal cancer cell lines harboring BRAF V600E resulted in suppression of colony formation in culture, and inhibition of tumor growth in a cell line xenograft model (PMID: 33568355). 33568355
BRAF V600E colorectal cancer sensitive Dabrafenib + LXH 254 + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, combination treatment with LXH 254, Tafinlar (dabrafenib), and Mekinist (trametinib) in colorectal cancer cell lines harboring BRAF V600E resulted in suppression of colony formation in culture, and inhibition of tumor growth in a cell line xenograft model (PMID: 33568355). 33568355
BRAF V600E melanoma sensitive Dabrafenib + Regorafenib + Trametinib Preclinical - Pdx & cell culture Actionable In a preclinical study, combination treatment with Stivarga (regorafenib), Tafinlar (dabrafenib), and Mekinist (trametinib) in a melanoma cell line harboring BRAF V600E resulted in suppression of colony formation in culture, and suppressed tumor growth in patient-derived xenograft (PDX) models (PMID: 33568355). 33568355
BRAF V600E melanoma sensitive Dabrafenib + RAF709 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with RAF709, Tafinlar (dabrafenib), and Mekinist (trametinib) in melanoma cell line harboring BRAF V600E resulted in suppression of colony formation in culture (PMID: 33568355). 33568355