PI3K inhibitors suppress c-Myc induction and enhance ADI-mediated cell killing and in animal models of argininosuccinate synthetase (AS, the rate-limiting enzyme for arginine biosynthesis)-negative melanoma, combination therapy using a PI3K inhibitor together with ADI-PEG20 yielded additive antitumor effects as compared with either agent alone. Here, PIK3CD is linked to melanoma.