ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms

Abstract

Oncogenic fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ( ) was reported in 11% of melanomas but the response of melanomas expressing to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for mRNA and protein expression. expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) and/or and one mucosal melanoma expresses multiple novel fusion variants. Melanoma cells expressing different variants were tested for response to ALK inhibitors. Whereas the melanoma expressing were sensitive to ALK inhibitors and, the melanomas expressing wt or were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing do not respond to ALK inhibitors. Targeting fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt or.

Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma

“…Cell lines were verified by short tandem repeat analysis and BRAF and NRAS mutation status was determined using the COSMIC database (34,35). MB2141, MB2204, and MB2724 were derived as previously described (36). Cell lines were tested for Mycoplasma contamination using a PCR-Based Kit (ATCC) and confirmed negative within 20 passages or 3 months before use.…”

Correlation of novel ALKATI with ALK immunohistochemistry and clinical outcomes in metastatic melanoma

“…15 Subsequent studies have reported ALK ATI expression in 0-15.6% of metastatic melanomas. 24,25 Interestingly, Uguen et al identified that 0% of cases showed IHC expression in a prospective series of 133 patients' metastases. 24 This may be due to regional variations, as noted in the manuscript; however, it is of note that the authors used a different ALK IHC antibody (5A4 clone).…”

Spitzoid Melanoma-Case Report; Potential Role of Alk Expression in the Diagnosis of Spitzoid Melanocytic Lesions

“…ALK was fi rst identifi ed as the protein product of an abnormal fusion gene produced by a specifi c chromosomal translocation in anaplastic large cell lymphoma (21). Later, it was identifi ed in other neoplasms, either benign or malignant, such as lung adenocarcinoma, Ewing sarcoma, infl ammatory myofbroblastic tumor, epithelioid fi brous histiocytomas (22). ALK was also detected in approximately 10-15% of all spitzoid tumors; ALK fusions are found in benign Spitz naevi, atypical Spitz tumors, and less commonly in spitzoid melanoma (23)(24)(25)(26).…”