Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer

ABSTRACT

Colorectal 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.

KEYWORDS:

• colorectal cancer (CRC)
• crizotinib
• mitomycin C (MMC)
• PARP inhibitor

Conflict of interest

J.X. is an employee of Caris Life Sciences. The other authors did not declare any conflict of interest regarding this manuscript. Dr. El-Deiry serves as the Editor-in-Chief of Cancer Biology and Therapy. Manuscripts submitted for peer review by the Editor-in-Chief of Cancer Biology and Therapy are automatically redacted during peer review and not visible to the Editor-in-Chief for details of manuscript handling or decision processing. The Editor-in-Chief plays no role in decisions involving their own submitted manuscripts. For those manuscript submissions, the manuscripts are assigned to a senior editor who oversees the review process and decisions.

Acknowledgments

This work was presented in part at the 2015 annual ASCO and 2016 annual AACR meetings. W.S.E-D. is an American Cancer Society Research Professor.