PI3Kα inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment

Radiotherapy is one of the standard therapies for esophageal squamous cell carcinoma (ESCC), but the efficacy is far from desirable. Large scale genome sequencing reveals PI3K alpha is frequently hyper-activated in ESCC. We found that ESCC cells harboring alterations in PI3K pathway were more resistant to radiation and combination of a clinical PI3K alpha-selective inhibitor CYH33 and radiation synergistically inhibited cell proliferation in 14 ESCC cell lines. Radiation induced phosphorylation of FOXO1 and Akt, which sensitized ESCC cells to PI3K alpha inhibitors. Both S1PR3 and DNA-PK contributed to radiation-induced Akt phosphorylation, which were revealed to be collectively dependent on PI3K alpha. By contrast, constitutively active Akt abrogated the synergism between PI3K alpha inhibitors and radiation. PI3K alpha inhibition enhanced radiation-induced DNA damage, G2/M arrest and apoptosis. Combination of CYH33 and radiation significantly inhibited the growth of xenografts derived from ESCC patients, which was accompanied with abrogation of radiation-induced phosphorylation of Akt and filtration of M2-like macrophages. Taken together, combination of CYH33 and radiation possesses synergism in ESCC, which provides promising rationale to test this combinatorial regimen in ESCC patients.