Co‐targeting of ALK and PI3Kβ lead to blockade of both MAPK and PI3K‐AKT signaling, attenuated EGFR‐mediated adaptive resistance, and elicited tumor cell‐selective toxicity with efficacy even in TP53 mutant ALK‐rearranged cells that had undergone EMT. Here, AKT1 is linked to neoplasm.