Identifying Novel Drug Targets in Melanoma

Resistance is a major problem that prevents long-term survival for patients with metastatic melanoma. We show that Abl kinases are activated by BRAF and Src, and drive resistance to BRAF/MEK inhibitors. Moreover, inhibitors of Abl/Arg and Akt, a pathway associated with resistance, cooperate to block mutant BRAF/PTEN melanoma growth, in vivo. We will test the following hypotheses: i) ERK activation by NRAS->CRAF or BRAF plays a critical role in activating Abl/Arg (Aim 1A); Abl/Arg are further activated in patient samples following resistance to ERK pathway therapy (Aim 1B); Abl/Arg inhibitor combinations effectively treat resistance by influencing cancer stem cell expansion (Aim 2).