We found that HRASG12S mutant was associated with resistance to PI3Kα inhibitors in ESCC cells by the three lines of evidences: firstly, ectopic expression of HRASG12S in ESCC cells significantly enhanced MAPK signaling and rendered resistance to CYH33; secondly, knockdown of HRASG12S or inhibition of signaling downstream of HRAS sensitized resistant cells to CYH33; thirdly, combination of CYH33 and MEK inhibitor synergistically inhibited the growth of xenografts that have originated from resistant cells harboring HRASG12S. This evidence concerns the gene MAP2K7 and esophageal squamous cell carcinoma.