In the preceding funding period we have identified recurrent mutations and copy number increases of KIT in 30-40% of melanomas arising on chronically sun-damaged skin (CSD), acral sites. Emerging clinical evidence indicates that these genetic alterations are a strong indicator for clinical responses to already approved KIT inhibitors. By contrast, KIT alterations are absent in melanoma arising on the non-CSD skin, which frequently harbor BRAF mutations, identifying them as biologically distinct. Differences in mutation spectra, chromosomal aberrations, and clinical and histopathological presentation implicate the KIT pathway as an important contributor in acral, mucosal, and CSD melanoma types. Despite these advances, the oncogenic alterations in the majority of these melanomas are currently not known as they infrequently harbor BRAF mutations. Preliminary studies implicate additional genes downstream of KIT as candidate genes, including the scaffolding protein GAB2, the protein phosphatase SHP2, amplification of the two p70S6 kinase genes as additional targets for somatic activation. We hypothesize that together these findings indicate a wider role for KIT pathway activation in these melanoma types, which would have therapeutic and diagnostic implications. We will validate the contribution of genetic alterations in the KIT pathway to the malignant phenotype and response to therapy and aim to discover additional alterations. Our studies will involve comprehensive genomic characterization of archival tissues to identify genetic alterations and determine in which combination they occur (aim 1), functional analyses in vitro models representing the most common of the findings in human tumors to characterize their effect on sensitivity and resistance to targeted agents (aim 2), and tumor samples from patients with KIT alterations who were treated with KIT inhibitors, to determine factors of primary and secondary resistance to treatment in a clinical setting (aim 3).
Characterization of the somatic genetic alterations in melanoma and their role in oncogenesis, therapeutic targets or biomarkers for resistance to specific therapies is of direct clinical relevance for the treatment and management of patients with metastatic melanoma.
|Talevich, Eric; Shain, A Hunter; Botton, Thomas et al. (2016) CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing. PLoS Comput Biol 12:e1004873|
|Lu, Hezhe; Liu, Shujing; Zhang, Gao et al. (2016) Oncogenic BRAF-Mediated Melanoma Cell Invasion. Cell Rep 15:2012-24|
|Krepler, Clemens; Xiao, Min; Samanta, Minu et al. (2016) Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma. Oncotarget :|
|Shannan, Batool; Chen, Quan; Watters, Andrea et al. (2016) Enhancing the evaluation of PI3K inhibitors through 3DÂ melanoma models. Pigment Cell Melanoma Res 29:317-28|
|Krepler, Clemens; Xiao, Min; Sproesser, Katrin et al. (2016) Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin Cancer Res 22:1592-602|
|Yeh, Iwei; Tee, Meng Kian; Botton, Thomas et al. (2016) NTRK3 kinase fusions in Spitz tumours. J Pathol 240:282-290|
|Shannan, Batool; Perego, Michela; Somasundaram, Rajasekharan et al. (2016) Heterogeneity in Melanoma. Cancer Treat Res 167:1-15|
|Cierlitza, Monika; ChauvistrÃ©, Heike; Bogeski, Ivan et al. (2015) Mitochondrial oxidative stress as a novel therapeutic target to overcome intrinsic drug resistance in melanoma cell subpopulations. Exp Dermatol 24:155-7|
|Qin, Jie; Rajaratnam, Rajathees; Feng, Li et al. (2015) Development of organometallic S6K1 inhibitors. J Med Chem 58:305-14|
|Carvajal, Richard D; Lawrence, Donald P; Weber, Jeffrey S et al. (2015) Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. Clin Cancer Res 21:2289-96|
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