Activation of protein phosphatase 2A (PP2A) is a promising anti-cancer therapeutic strategy given this tumor suppressor’s ability to coordinately downregulate multiple pathways involved with growth and proliferation.Here, we studied the global signaling response signature of a novel small molecule activator of PP2A (SMAP). Through an exploration of the global phosphoproteomicalterations of two KRAS mutated non-small cell lung cancer (NSCLC) cell lines (A549 and H358)in the context of PP2A activation, we sought to identify the pathway-level perturbations and uncover candidate proteins that are potentially key targets of SMAP regulation.