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Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer
Cancer Biol Ther. 2017 Sep 2;18(9) :694-704
PMID: 28886275 PMCID: PMC5663405 URL: https://www.ncbi.nlm.nih.gov/pubmed/28886275
AbstractColorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. We analyzed 26 MSI-High and 558 non-MSI-High CRC tumors. BRCA2 mutations were highly enriched (50%) in MSI-High CRC. Immunohistochemistry showed that BRCA2-mutated MSI-High CRC had high c-MET (64%) expression compared with BRCA-WT (17%). We hypothesized a mechanistic link between BRCA2-deficiency and c-MET overexpression and synergistic interaction between drugs that treat BRCA-deficient tumors (mitomycin C (MMC) or PARP inhibitors) and c-MET inhibitors (crizotinib). We tested CRC cell lines for sensitivity to MMC plus crizotinib or other drug combinations including PARP-inhibitors. Combined treatment of tumor cells with crizotinib and MMC led to increased apoptosis as compared with each drug alone. Additionally, combination treatment with increasing concentrations of both drugs demonstrated a synergistic anti-cancer effect (CI = 0.006-0.74). However, we found no evidence for c-MET upregulation upon effective BRCA2 knockdown in tumor cells -/+DNA damage. Although we found no mechanistic link between BRCA2 deficiency and c-MET overexpression, c-MET is frequently overexpressed in CRC and BRCA2 is mutated especially in MSI-H CRC. The combination of crizotinib with MMC appeared synergistic regardless of MSI or BRCA2 status. Using an in-vivo CRC xenograft model we found reduced tumor growth with combined crizotinib and MMC therapy (p = 0.0088). Our preclinical results support clinical testing of the combination of MMC and crizotinib in advanced CRC. Targeting cell survival mediated by c-MET in combination with targeting DNA repair may be a reasonable strategy for therapy development in CRC or other cancers.
Notes1555-8576 Lev, Avital ORCID: http://orcid.org/0000-0002-2127-7338 Deihimi, Safoora Shagisultanova, Elena Xiu, Joanne Lulla, Amriti R ORCID: http://orcid.org/0000-0002-7085-5755 Dicker, David T El-Deiry, Wafik S Journal Article United States Cancer Biol Ther. 2017 Sep 8:1-11. doi: 10.1080/15384047.2017.1364323.