Sunitinib Therapy for Melanoma Patients with KIT Mutations

Abstract

Purpose: Recent studies have shown activating KIT mutations in melanoma originating from mucosa, acral, or cumulative sun-damaged skin sites. We aimed to assess the predictive role of KIT mutation, amplification, or overexpression for response to treatment with the kinase inhibitor sunitinib.Experimental Design: Tumor tissues from 90 patients with stage III or IV acral, mucosal, or cumulative sun-damaged skin melanoma underwent sequencing of KIT, BRAF, NRAS, and GNAQ genes, FISH analysis for KIT amplification, and immunohistochemistry of KIT protein (CD117). Patients with mutations, amplifications, or overexpression of KIT were treated with sunitinib and responses measured by Response Evaluation Criteria in Solid Tumors (RECIST).Results: Eleven percent of the melanomas tested had mutations in KIT, 23% in BRAF, 14% in NRAS, and none in GNAQ. Of 12 patients treated with sunitinib, 10 were evaluable. Of the 4 evaluable patients with KIT mutations, 1 had a complete remission for 15 months and 2 had partial responses (1-and 7-month duration). In contrast, only 1 of the 6 patients with only KIT amplification or overexpression alone had a partial response. In 1 responder with rectal melanoma who later progressed, the recurring tumor had a previously undetected mutation in NRAS, which was found in addition to the persisting mutation in KIT. Interestingly, among patients with manifest stage IV disease, KIT mutations were associated with a significantly shortened survival time (P < 0.0001).Conclusions: Sunitinib may have activity in patients with melanoma and KIT mutations; more study is needed. KIT mutations may represent an adverse prognostic factor in metastatic melanoma.

Dual modulation of MCL-1 and mTOR determines the response to sunitinib

“…As a competitive ATP antagonist, sunitinib inhibits the phosphorylation of several tyrosine kinase receptors including VEGFR, PDGFR, and stem cell factor receptor (c-KIT) (1). Sunitinib is approved for treating patients with advanced renal cell carcinoma (2), pancreatic neuroendocrine tumors (3), and gastrointestinal stromal tumors (4,5) and is being tested in other types of cancer including osteosarcoma (6), colorectal cancer (7), and melanoma (8). However, a substantial percentage of patients are intrinsically resistant to sunitinib, and most patients who show initial response to treatment with sunitinib eventually relapse and develop progressive disease secondary to acquired sunitinib resistance, resulting in a modest overall therapeutic benefit (9)(10)(11)(12)(13).…”

Two Cases of Primary Extracutaneous Melanoma: Primary Gastric Melanoma and Primary Melanoma of the Lung

“…The patient experienced a marked reduction in both the size and number of metastatic lesions over a four month treatment period [17]. Minor et al observed a complete remission for 15 months and two partial remissions lasting 1 month and 7 months when using sunitinib to treat mucosal melanomas [18]. No KIT testing was performed on our case report patient, but again, the promise of these therapies indicates that KIT testing should be standard of care for the management of extracutaneous melanomas.…”

A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth

“…24,25,27,28 Furthermore, the efficacy of these agents in other c-Kit positive tumors is not as evident, especially in SCLC and leukemia (AML) where clinical trials have failed in patients with relapsed or refractory disease, [30][31][32] and in melanoma where modest drug activity was reported predominantly in patients with mutant c-Kit tumors. 33,34 A function blocking antibody is an alternative approach to targeting c-Kit expressing cancers. Previous reports of c-Kit antibodies (e.g., YB5.B8, SR-1), 35,36 lacked extensive in vivo characterization and demonstrated potential for agonistic activity.…”

“…44 Similarly, in melanoma there are reports of aberrant c-Kit expression and presence of activating mutations in the acral and mucosal tumor subtypes. 15,23,33,34 The observed in vitro and in vivo sensitivity of c-Kit expressing melanomas to CK6 suggests this is an additional indication for antibody mediated therapy. A more extensive evaluation of c-Kit expression across a broader panel of primary tumor samples is warranted (along with tumor molecular profiling) to identify additional c-Kit positive cancer types eligible for CK6 preclinical efficacy testing which ultimately will provide a better understanding of patient population most suitable to receive and likely benefit from CK6 therapy in the clinic.…”