Reference Detail

Ref Type

Journal Article

PMID

(39001563)

Authors

Turner JA, Van Gulick RJ, Robinson WA, Mughal T, Tobin RP, MacBeth ML, Holman B, Classon A, Bagby SM, Yacob BW, Hartman SJ, Silverman I, Vorwald VM, Gorden N, Gonzalez R, Gay LM, Ali SM, Benson A, Miller VA, Ross JS, Pitts TM, Rioth MJ, Lewis KD, Medina T, McCarter MD, Gonzalez R, Couts KL

Title

Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of cancer			2024 Jul 12		Int J Cancer

URL

Abstract Text

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.

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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
NRAS Q61R	acral lentiginous melanoma	sensitive	Trametinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Mekinist (trametinib) treatment inhibited viability of patient-derived acral melanoma cells harboring NRAS Q61R in culture (PMID: 39001563).	39001563
NRAS G12D	acral lentiginous melanoma	predicted - sensitive	Tovorafenib	Case Reports/Case Series	Actionable	In a clinical case study, Ojemda (tovorafenib) treatment resulted in a partial response with therapy lasting at least 7.5 years in a patient with metastatic acral melanoma harboring NRAS G12D (PMID: 39001563).	39001563
NRAS Q61H	mucosal melanoma	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) treatment inhibited viability of patient-derived mucosal melanoma cells harboring NRAS Q61H in culture (PMID: 39001563).	39001563