Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	11	7	2021 Jul	1716-1735	Cancer Discov

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 well-being in a patient with stage IV colorectal cancer. Thus, exploiting allosteric properties of RAF and MEK inhibitors enables the design of effective and well-tolerated therapies for BRAF V600E tumors. SIGNIFICANCE: This work identifies a new class of RAFi that are selective for dBRAF over mBRAF and determines the basis of their selectivity. A rationally designed combination of RAF and MEK inhibitors based on their conformation selectivity achieved increased efficacy and a high therapeutic index when used to target BRAF V600E tumors. See related commentary by Zhang and Bollag, p. 1620 . This article is highlighted in the In This Issue feature, p. 1601 .

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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	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	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	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	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 + 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	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	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