Certain cancers, including gastrointestinal stromal tumor (GIST) and subsets of melanoma, are caused by somatic KIT mutations that result in constitutive KIT receptor tyrosine kinase activity to drive neoplastic growth. The treatment of these KIT-mutant cancers has been revolutionized with the advent of KIT-directed cancer therapies. KIT tyrosine kinase inhibitors (TKI), such as imatinib, are superior to conventional chemotherapy in their ability to control advanced KIT-mutant disease. However, these therapies have a limited duration of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) during KIT TKI treatment. Once patients become resistant to KIT TKIs, GIST patients have no other options. To solve the problem of KIT TKI resistance, I sought to identify novel therapeutic targets in KIT-mutant cells using a human tyrosine kinome silencing RNA (siRNA) screen.