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Ref Type

Journal Article

PMID

(29903896)

Authors

Dankner M, Lajoie M, Moldoveanu D, Nguyen TT, Savage P, Rajkumar S, Huang X, Lvova M, Protopopov A, Vuzman D, Hogg D, Park M, Guiot MC, Petrecca K, Mihalcioiu C, Watson IR, Siegel PM, Rose AAN

Title

Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant Melanomas.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	24	24	2018 Dec 15	6483-6494	Clin Cancer Res

URL

Abstract Text

Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi.Tumors from patients with BRAF wild-type (WT), V600E (class I), and L597S (class II) metastatic melanoma were used to generate patient-derived xenografts (PDX). We assembled a panel of melanoma cell lines with class IIa (activation segment) or IIb (p-loop) mutations and compared these with WT or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib, and LY3009120), MEKi (cobimetinib, trametinib, and binimetinib), or the combination. We identified 2 patients with BRAF L597S metastatic melanoma who were treated with dMAPKi.BRAFi impaired MAPK signaling and cell growth in class I and II BRAF mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma PDXs with class II BRAF mutations and prolonged survival of mice with class II BRAF mutant melanoma brain metastases. Two patients with BRAF L597S mutant melanoma clinically responded to dMAPKi.Class II BRAF mutant melanoma is growth inhibited by dMAPKi. Responses to dMAPKi have been observed in 2 patients with class II BRAF mutant melanoma. These data provide rationale for clinical investigation of dMAPKi in patients with class II BRAF mutant metastatic melanoma.See related commentary by Johnson and Dahlman, p. 6107.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	R239Q	missense	unknown	BRAF R239Q lies within the phorbol-ester/DAG-type zinc finger domain of the Braf protein (UniProt.org). R239Q has been identified in the scientific literature (PMID: 29903896), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Sep 2024).
BRAF	S363F	missense	unknown	BRAF S363F does not lie within any known functional domains of the Braf protein (UniProt.org). S363F has been identified in the scientific literature (PMID: 29903896), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Sep 2024).

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Showing 1 to 29 of 29 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF L597S	melanoma	sensitive	Dabrafenib + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, Tafinlar (dabrafenib) and Mekinist (trametinib) resulted in increased growth inhibition in melanoma cell lines harboring BRAF L597S in culture, and resulted in tumor shrinkage in 89% (17/19) of tumors in a patient-derived xenograft (PDX) model harboring BRAF L597S, and treatment with Tafinlar (dabrafenib) and Mekinist (trametinib) resulted in a objective response with 34% tumor shrinkage in the patient from which the PDX model was derived from (PMID: 29903896).	29903896
BRAF L597S	melanoma	predicted - sensitive	Dabrafenib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Tafinlar (dabrafenib) treatment inhibited ERK activation and proliferation of melanoma cell lines harboring BRAF L597S in culture, but did not result in tumor shrinkage as a single agent in a melanoma patient-derived xenograft (PDX) model harboring BRAF L597S (PMID: 29903896).	29903896
BRAF L597S	melanoma	predicted - sensitive	Trametinib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of melanoma cell lines harboring BRAF L597S in culture, and resulted in tumor shrinkage in 75% (8/12) subcutaneous tumors in one patient-derived xenograft (PDX) model harboring BRAF L597S that also harbored a BRAF variant of unknown significance, BRAF R239Q, however, was not sufficient to induce tumor shrinkage in a second PDX model with BRAF L597S, resulting only in tumor growth delay (PMID: 29903896).	29903896
BRAF R239Q BRAF L597S	melanoma	sensitive	Binimetinib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Mektovi (binimetinib) inhibited growth of patient-derived melanoma cells harboring BRAF L597S, as well as BRAF R239Q, in culture, and induced tumor shrinkage in 25% (3/12) of tumors and delayed tumor growth in a patient-derived xenograft (PDX) model (PMID: 29903896).	29903896
BRAF R239Q BRAF L597S	melanoma	sensitive	Binimetinib + Encorafenib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, the addition of Braftovi (encorafenib) to treatment with Mektovi (binimetinib) increased growth inhibition in patient-derived melanoma cells harboring BRAF L597S, as well as BRAF R239Q, in culture, and resulted in tumor shrinkage in 67% of tumors, increased inhibition of ERK phosphorylation, and increased tumor growth delay compared to either agent alone in a patient-derived xenograft (PDX) model (PMID: 29903896).	29903896
BRAF R239Q BRAF L597S	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, the addition of Tafinlar (dabrafenib) to treatment with Mekinist (trametinib) resulted in increased growth inhibition in a patient-derived melanoma cell line harboring BRAF L597S, as well as well as BRAF R239Q, in culture, and resulted in tumor shrinkage in 100% (13/13) of subcutaneous tumors, and decreased growth of intracranial tumors in a patient-derived xenograft (PDX) model (PMID: 29903896).	29903896
BRAF R239Q BRAF L597S	melanoma	sensitive	Encorafenib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Braftovi (encorafenib) inhibited ERK activation and proliferation of patient-derived melanoma cells harboring BRAF L597S, as well as BRAF R239Q, in culture, and delayed tumor growth and induced shrinkage in 8% (1/12) of tumors in a melanoma patient-derived xenograft (PDX) model (PMID: 29903896).	29903896
BRAF G469A	lung non-small cell carcinoma	conflicting	Trametinib + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Zelboraf (vemurafenib) to treatment with Mekinist (trametinib) resulted in increased proliferation compared to Mekinist (trametinib) alone in a non-small cell lung cancer cell line harboring BRAF G469A in culture (PMID: 29903896).	29903896
BRAF G469A	lung non-small cell carcinoma	sensitive	Encorafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Braftovi (encorafenib) to treatment with Mekinist (trametinib) resulted in increased growth inhibition in a non-small cell lung cancer cell line harboring BRAF G469A in culture (PMID: 29903896).	29903896
BRAF G469A	lung non-small cell carcinoma	sensitive	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Tafinlar (dabrafenib) treatment did not result in significant growth inhibition in a non-small lung cancer cell line harboring BRAF G469A in culture (PMID: 29903896).	29903896
BRAF G469V	melanoma	no benefit	Encorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Braftovi (encorafenib) did not inhibit ERK phosphorylation or proliferation of a melanoma cell line harboring BRAF G469V (PMID: 29903896).	29903896
BRAF G469V NRAS Q61K	melanoma	sensitive	Binimetinib + Encorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Braftovi (encorafenib) to treatment with Mektovi (binimetinib) resulted in increased growth inhibition in a melanoma cell line harboring BRAF G469V and NRAS Q61K in culture (PMID: 29903896).	29903896
BRAF G469V NRAS Q61K	melanoma	sensitive	Encorafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Braftovi (encorafenib) to treatment with Mekinist (trametinib) resulted in increased growth inhibition in a melanoma cell line harboring BRAF G469V and NRAS Q61K in culture (PMID: 29903896).	29903896
BRAF G469V NRAS Q61K	melanoma	predicted - resistant	Trametinib + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Zelboraf (vemurafenib) to treatment with Mekinist (trametinib) resulted in increased proliferation compared to Mekinist (trametinib) alone in a melanoma cell line harboring BRAF G469V and NRAS Q61K in culture (PMID: 29903896).	29903896
BRAF G469V NRAS Q61K	melanoma	no benefit	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Tafinlar (dabrafenib) treatment did not result in significant growth inhibition in a melanoma cell line harboring BRAF G469V and NRAS Q61K in culture (PMID: 29903896).	29903896
BRAF G469V NRAS Q61K	melanoma	sensitive	LY3009120	Preclinical - Cell culture	Actionable	In a preclinical study, LY3009120 inhibited growth of a melanoma cell line harboring BRAF G469V and NRAS Q61K in culture (PMID: 29903896).	29903896
BRAF L597S	melanoma	sensitive	LY3009120	Preclinical - Cell culture	Actionable	In a preclinical study, LY3009120 inhibited growth of melanoma cells harboring BRAF L597S in culture (PMID: 29903896).	29903896
BRAF L597S	melanoma	sensitive	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mektovi (binimetinib) inhibited growth of melanoma cell lines harboring BRAF L597S in culture (PMID: 29903896).	29903896
BRAF L597S	melanoma	sensitive	Cobimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Cotellic (cobimetinib) inhibited growth of melanoma cell lines harboring BRAF L597S in culture (PMID: 29903896).	29903896
BRAF L597S	melanoma	sensitive	Binimetinib + Encorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Braftovi (encorafenib) to treatment with Mektovi (binimetinib) resulted in increased growth inhibition in melanoma cell lines harboring BRAF L597S in culture (PMID: 29903896).	29903896
BRAF L597S	melanoma	sensitive	Encorafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Braftovi (encorafenib) to treatment with Mekinist (trametinib) resulted in increased growth inhibition in melanoma cell lines harboring BRAF L597S in culture (PMID: 29903896).	29903896
BRAF L597S	melanoma	sensitive	Encorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Braftovi (encorafenib) inhibited ERK activation and proliferation of melanoma cell lines harboring BRAF L597S in culture (PMID: 29903896).	29903896
BRAF S363F BRAF K601E	melanoma	sensitive	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mektovi (binimetinib) inhibited growth of a melanoma cell line harboring BRAF K601E, as well as BRAF S363F, in culture (PMID: 29903896).	29903896
BRAF S363F BRAF K601E	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Tafinlar (dabrafenib) to treatment with Mekinist (trametinib) resulted in increased growth inhibition in a melanoma cell line harboring BRAF K601E, as well as BRAF S363F, in culture (PMID: 29903896).	29903896
BRAF S363F BRAF K601E	melanoma	sensitive	Cobimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Cotellic (cobimetinib) inhibited growth of a melanoma cell line harboring BRAF K601E, as well as BRAF S363F, in culture (PMID: 29903896).	29903896
BRAF S363F BRAF K601E	melanoma	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of a melanoma cell line harboring BRAF K601E, as well as BRAF S363F, in culture (PMID: 29903896).	29903896
BRAF S363F BRAF K601E	melanoma	sensitive	Encorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Braftovi (encorafenib) inhibited growth of a melanoma cell line harboring BRAF K601E, as well as BRAF S363F, in culture (PMID: 29903896).	29903896
BRAF S363F BRAF K601E	melanoma	sensitive	Trametinib + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Zelboraf (vemurafenib) to treatment with Mekinist (trametinib) resulted in increased growth inhibition in a melanoma cell line harboring BRAF K601E, as well as BRAF S363F, in culture (PMID: 29903896).	29903896
BRAF S363F BRAF K601E	melanoma	sensitive	Encorafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Braftovi (encorafenib) to treatment with Mekinist (trametinib) resulted in increased growth inhibition in a melanoma cell line harboring BRAF K601E, as well as BRAF S363F, in culture (PMID: 29903896).	29903896

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