Inibitori di PARP come modulatori della resistenza alla chemioterapia

Poly(ADP-ribose) polymerase (PARP) inhibitors as modulators of tumor drug resistance to chemotherapy. Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising class of anticancer agents currently in clinical trials either in combination with chemotherapy [e.g., the methylating compound temozolomide (TMZ), the topoisomerase I (TOPO I) poisons irinotecan (CPT-11) or topotecan] and radiotherapy or as monotherapy. In fact, PARP inhibitors exert cytotoxic effects as single agents in BRCA mutated tumors, which are defective in the homologous recombination repair (HR) of DNA double strand breaks (DSBs). In preclinical models we have demonstrated that PARP inhibitors enhance the antitumor activity of TMZ or of TOPO I inhibitors especially in mismatch repair (MMR) deficient tumors, including colorectal cancer that is frequently characterized by MMR dysfunction. Moreover, the PARP inhibitor GPI 15427 increases the efficacy also of CPT-11 and TMZ combination against MMR deficient colon cancer in vitro and in tumor xenografts. hMLH1 is mainly involved in the processing of O6-methylguanine:C/T mispairs responsible for the cytotoxic effects of TMZ. Recently, it has been suggested that MSH3 might be involved in the repair of DSBs induced by intra-strand cross-links provoked by platinum derivatives through the intervention of HR. The role of the different MMR components in the susceptibility of colon cancer cells to TOPO I poisons have not been clarified, yet. The human colon cancer cell lines HCT116 (known to have a homozygous mutation in the MMR hMLH1 gene on chromosome 3 and homozygous frameshift mutations in the MMR hMSH3 gene on chromosome 5), the HCT116 derived cell lines in which only the wild-type hMLH1 (HCT116+3) or both the wild-type hMLH1 and hMSH3 genes (HCT116+3+5) have been replaced, via chromosome transfer, were used to test their susceptibility to anticancer drugs with different mechanisms of action. The hMLH1 and hMSH3 deficient HCT116 cells and the HCT116+3+5 cells were more sensitive to SN38 (the active metabolite of CPT-11) than HCT116+3 cells that, instead, were highly sensitive to TMZ. Interestingly, the hMLH1 and hMSH3 proficient HCT116+3+5 cells were more resistant to oxaliplatin than the other cell lines. HCT116, characterized by a higher PARP-1 expression with respect to the other cell lines, were the most sensitive to the PARP inhibitor GPI 15427 as single agent. Stable silencing of PARP-1 expression resulted in increased chemosensitivity. The results suggest that that hMLH1, hMSH3 or PARP-1 status may predict differential sensitivity to chemotherapeutic agents.