Mtor Pathway Activation In Kit-Mutated Melanoma With Acquired Imatinib Resistance.

8562 Background: c-Kit mutation is a common genetic abnormality in certain melanoma subtypes, and is a target for treatment. However, the mechanisms of secondary (acquired) resistance and how to treat patients in the second line are unknown. Methods: Tissuesamples were obtained from c-Kit-mutated melanoma patients who failed of imatinib after having PR or SD for at least 6 months pre- and post-imatinib therapy. Somatic mutations in genes in MAP kinase (c-Kit, BRAF, NRAS, etc) and PI3K-AKT-mTOR (AKT1, TSC1, PTEN, etc) pathways were detected by DNA sequencing. The expression of pS6RP, p4E-BP1, pAKT and pERK1/2 were examined by immunohistochemistry (IHC) assays. Results: Four paired samples (formalin-fixed, paraffin-embedded) were analyzed. 1) Laboratory results: No secondary mutations in addition to the c-Kit mutations identified at baseline were identified. However, IHC showed increased pS6RP and p4E-BP1 (two targets of mTOR activation) as well as increased pAKT and pERK1/2 in imatinib-resistant samples, s...