The GIST of targeted therapy for malignant melanoma

Abstract

The high response rates to the tyrosine kinase inhibitor imatinib in KIT-mutated gastrointestinal stromal tumors (GIST) has led to a paradigm shift in cancer treatment. In a parallel fashion, the field of melanoma is shifting with the utilization of targeted therapy to treat BRAF-mutated melanoma. We reviewed published literature in PubMed on GIST and melanoma, with a focus on both past and current clinical trials. The data presented centers on imatinib, vemurafenib, and most recently dabrafenib, targeting KIT and BRAF mutations and their outcomes in GIST and melanoma. The BRAF(V600E) melanoma mutation, like the KIT exon 11 mutation in GIST, has the highest response to therapy. High response rates with inhibition of KIT in GIST have not been recapitulated in KIT-mutated melanoma. Median time to resistance to targeted agents occurs in ~7 months with BRAF inhibitors and 2 years for imatinib in GIST. In GIST, the development of secondary mutations leads to resistance; however, there have been no similar gatekeeper mutations found in melanoma. Although surgery remains an important component of the treatment of early GIST and melanoma, surgeons will need to continue to define the thresholds and timing for operation in the setting of metastatic disease with improved targeted therapies. Combination treatment strategies may result in more successful clinical outcomes in the management of melanoma in the future.

FIG. 1

Structure of KIT and PDGFRA and distribution of identified mutations in GIST

FIG. 2

Normal activation of MAPK pathway and pathway response to RAF inhibition. a Normal activation of the wild-type cell RAS–RAF–MEK–ERK pathway promotes cell growth. b Mutations of the MAPK pathway, especially those of oncogenic BRAF^V600E in melanoma, result in enhanced signaling in the MAPK pathway and eventual tumor formation and growth. In the presence of a BRAF inhibitor that blocks BRAF, MEK– ERK signaling in BRAF^V600E mutant cells is suppressed, causing tumor shrinkage. RTK receptor tyrosine kinase (e.g., KIT, FLT2, PDGF, VEGF), RAS rat sarcoma, RAF rapidly accelerated fibrosarcoma, MEK MAPK/ERK kinase, ERK extracellular signal– regulated kinase

FIG. 3

Structure of KIT and distribution of identified mutations in melanoma. KIT mutations are found in 2–6 % of all malignant melanoma, mostly in the acral and mucosal subtypes

FIG. 4

Neoadjuvant vemurafenib. A patient with primary melanoma of the leg presented with bulky superficial and deep inguinal nodes (a red arrows). A BRAF^V600E mutation was noted, and a metastatic disease assessment was negative. The patient initiated neoadjuvant vemurafenib therapy, with significant reduction in the size of the lymphadenopathy at 12 weeks (b yellow arrows), at which time he underwent lymph node dissection. Pathology revealed three positive nodes, and the BRAF^V600E mutation was detected in the posttreatment specimen. The patient subsequently developed brain metastasis