Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT-737 on Head and Neck Squamous Cell Carcinoma

International audienceIntrinsic radioresistance of cancer cells remains a fundamental barrier to obtain the maximal efficacy of radiotherapy (RT) for the treatment of HNSCC. This resistance to RT is due, in large part, to aberrant inhibition of apoptosis through overexpression and/or hyperactivation of signaling proteins and pathways. Among these, some members of the Blc-2 protein family, such as Bcl-2 and Bcl-XL, contribute this resistance by inhibiting the intrinsic mitochondrial pathway. ABT-737 is a rationally designed small molecule that binds with high affinity to Bcl-2 and Bcl-XL and antagonizes their anti-apoptotic function, thereby inducing apoptosis in many cancer cell types. Although ABT-737 has been shown to make HNSCC cells more susceptible to conventional chemotherapy, no prior study investigating the effect of ABT-737 in combination with RT has been undertaken for the treatment of HNSCC.We investigated the effect of ABT-737 combined to radiation on 4 HNSCC cell lines of graduate sensitivity. All of them strongly express BcL-Xl and Bcl-2 at a lesser extent, two primary targets of ABT-737, and a good correlation was obtained between the pro-apoptotic protein Bak expression and the survival fraction at 2Gy of the cell lines. Although ABT-737 is modestly effective as a monotherapy against HNSCC, isobolographic analysis demonstrated that it potently synergizes with RT to kill tumor cells through the intrinsic apoptotic pathway. We also investigated the potential of this therapeutic association on cancer stem cells (CSCs) obtained from the SQ20B cell line. A strong radiosensitizing effect was obtained with ABT-737 alone but combination with RT resulted in a very efficient CSC killing. Finally, the combination of ABT-737 to RT resulted in a significant tumor growth delay in a mouse xenograft model.Altogether, these data demonstrate potent synergy between ABT-737 and RT in the killing of HNSCC cells and reveal a promising therapeutic benefit including inhibition of tumor relapse.Supported by ANR-11-LABX-0063, Lyric Grant INCa-DGOS-4664 and CPER ETOILE