NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy

SIMPLE SUMMARY: Resistance to chemoradiotherapy represents a fundamental problem in modern oncology because it exposes patients to the potential negative side-effects of both radiation and chemotherapy without any clinical benefit. This study uncovers that the inflammatory signaling hub STAT3 conspires with the cell fate regulator NOTCH in rendering tumor cells refractory to chemoradiotherapy. The dichotomic signal alliance is based on a so-far unknown STAT3 target gene, RBPJ, providing the transcriptionally active partner of NOTCH intracellular domain. Unexpectedly, the latter is permanently produced by tonic proteolysis. Tumor mouse models and cancer patient cohorts demonstrate the usefulness of the STAT3/NOTCH axis as biomarker for patient stratification, and importantly, that STAT3 inhibition is a promising treatment option for re-sensitization of CRT-refractory tumors. ABSTRACT: Resistance of tumor cells to chemoradiotherapy represents a fundamental problem in clinical oncology. The underlying mechanisms are actively debated. Here we show that blocking inflammatory cytokine receptor signaling via STAT3 re-sensitized treatment-refractory cancer cells and abolished tumor growth in a xenograft mouse model when applied together with chemoradiotherapy. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. The mandatory RBPJ interaction partner, NOTCH intracellular domain, was provided by tumor cell-intrinsic expression of NOTCH ligands that caused tonic NOTCH proteolysis. In fact, NOTCH inhibition phenocopied the effect of blocking STAT3 signaling. Moreover, genetic profiling of rectal cancer patients revealed the importance of the STAT3/NOTCH axis as NOTCH expression correlated with clinical outcome. Our data uncovered an unprecedented signal alliance between inflammation and cellular development that orchestrated resistance to chemoradiotherapy. Clinically, our findings allow for biomarker-driven patient stratification and offer novel treatment options.