164 - Combined STAT3 and ERK1/2 inhibition synergizes with radiation to eliminate radioresistant glioblastoma cells

Abstract

Radioresistance is a major cause of post-surgery treatment failure in glioblastoma multiforme (GBM). Here, according to the immunodetection in 34 paired (both of primary and recurrent samples were aquired from the same patient) clinical GBM samples and multiple radioresisitant GBM clones as well as breast cancer, lung cancer cell lines, we reveal a positive relationship between pSTAT3 (Y705) and GBM radioresistance, since pSTAT3 (Y705) was significantly enhanced in most of the recurrent tumor tissues or cells survived mimic clinical radiation treatment compared with their corresponding primary counterparts, respectively. Likewise, relapse-free survival analysis of TCGA patients shows that STAT3 expression contributes to GBM radioresistance (p = 0.0007). However, blocking pSTAT3 (Y705) with inhibitors or genetic mutation/deletion cannot achieve a maximal radiosensitization as expected because ERK1/2 signaling was re-activated to drive cells survive treatments. Notably, an additional pharmacological inhibition of ERK1/2 together with pSTAT3 (Y705) blockade significantly eradicated radioresistant cells in the presence of radiation. Considering many drugs currently used for anti-tumor therapies affect STAT3 activation and an array of STAT3 inhibitors are undergoing clinical trials for tumor treatment. These findings indicate that an ERK1/2 feed back loop may impede the response of pSTAT3 (Y705)-addicted radioresisitant GBM cells to a broad spectrum of drugs targeting pSTAT3 (Y705).