Sensitization of colorectal cancer cells to irinotecan by the Survivin inhibitor LLP3 depends on XAF1 proficiency in the context of mutated p53.

Abstract

Survivin is a well-established target in experimental cancer therapy. While hardly expressed in normal tissues, it is over-expressed in most human tumors, including colorectal cancer (CRC). Different compartmentalization of Survivin enables its multiple functions as a key controller of cell division, apoptosis, stress-induced signaling and also of migration and metastasis. Because of the lack of its enzymatic activity, this oncoprotein is considered to be undruggable. Nevertheless, small-molecule interfacial inhibitors interfering with its dimerization and/or disrupting the Survivin-Ran protein complex were shown to be potent drugs causing Survivin proteasomal degradation and inducing apoptosis in cancer cells. Based on our results with different CRC cell lines, we show that the Survivin inhibitor LLP3 might be effective as mono-therapy in the subgroup of p53-proficient and also some p53-mutated tumors, independent of mismatch repair status. When combined with irinotecan, expression of the tumor suppressor X-linked inhibitor of apoptosis factor 1 (XAF1) plays a decisive role for sensitization of CRC cells to this first-line drug, however, only in the p53-mutated background. The combination treatment with IT should be avoided in p53-proficient tumors independent of XAF1 expression, since no sensitization to or even protection against moderate-toxic concentrations of IT might occur.