phd1-mediated chemotherapy resistance implications in colorectal cancer

Abstract

PROBLEM: Resistance to chemotherapy remains a major clinical issue in the treatment of colorectal cancer (CRC) and other cancer types. Response rates in patients with metastatic CRC have already improved to about 30-40% over the past years with the introduction of the FOLFOX and FOLFIRI treatment regimens. However, there is still much room for improvement and thus further research on potential candidates causing chemorefractory disease. RESULTS: We demonstrate that PHD1 mediates CRC resistance against 5-FU, irinotican and oxaliplatin by favoring p38α-mediated p53 phosphorylation. This post-translational modification of p53 allows the interaction between p53 and XPB, a component of the nucleotide excision repair machinery, ultimately leading to the resolution of DNA damage caused by these genotoxic drugs which enables cancer cells to survive and proliferate. By inhibiting PHD1 in CRC cells carrying wild-type or DNA-contact mutant p53, we show increased cell death in response to chemotherapy and improved disease outcome in mouse models of CRC. IMPACT: Our data support the design, validation and use of PHD1-specific inhibitors in colorectal cancer patients carrying wild-type or DNA-contact mutant p53, with the aim to increase sensitivity to currently used chemotherapeutic treatments.status: publishe