Lung cancer is one of the most prevalent cancers worldwide. This study focused on small cell lung cancer (SCLC), which has a poor clinical prognosis, and attempted to elucidate potential therapeutic molecular targets. A target-specific mutational search revealed mutation of the PIK3CA gene in three of 13 SCLC cell lines and two of 15 primary SCLCs. By introducing these mutant PIK3CA cDNAs, we established artificial "PIK3CA-addicted" cells and found that Tricribine, a small-molecule inhibitor of AKT signaling that is located downstream from PIK3CA, significantly inhibited the growth and colony formation activity of these cells. Using cancer cell lines, we further showed that PIK3CA-mutated SCLC cells are more sensitive to Tricribine than PIK3CA wild-type cells. Additionally, we found that a cisplatin-resistant subclone of PIK3CA-mutant SCLC cells was equally sensitive to Tricribine. This study for the first time uncovered PIK3CA alterations in SCLC, and our findings suggest that anti-AKT molecular therapy could be effective for a subgroup of SCLC, which shows activation of specific genes, such as PIK3CA mutation, and that genetic stratification of SCLC according to the activation status of individual therapeutic target pathways could be clinically beneficial, especially for chemotherapy-resistant/relapsing tumors.