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 PI3Kα 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 PI3Kα-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 PI3Kα inhibitors. Both S1PR3 and DNA-PK contributed to radiation-induced Akt phosphorylation, which were revealed to be collectively dependent on PI3Kα. By contrast, constitutively active Akt abrogated the synergism between PI3Kα inhibitors and radiation. PI3Kα 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. •ESCC cells harboring alterations in PI3K pathway were more resistant to radiation.•Combination of radiation and PI3Kα inhibitors displayed synergistic activity against ESCC cells and PDXs.•The synergism was associated with abrogation of pro-survival signals in tumor cells and tumor-associated macrophages.