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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 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
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