Investigators Seek Method to Overcome Chemotherapy Resistance

Blocking oxygen sensor may improve colorectal cancer treatment.

Overcoming resistance to chemotherapy is an ongoing dilemma for cancer investigators to solve.

To seek the answer to this problem, researchers have recently begun to target the underlying mechanisms that drive chemotherapy resistance. A study published in EMBO Molecular Medicine evaluated the interaction between the p53 and PHD group of oxygen sensors to examine the possible role in how colorectal cancer responds to chemotherapy.

The PHD1, PHD2, and PHD3 proteins are oxygen-sensitive enzymes implicated in causing damage to cells and metabolic stress, including during chemotherapy treatment. When it mutates in cancer cells, the transcription factor p53 can start to actively promote DNA repair to decrease the efficacy of chemotherapy.

For the current study, researchers found that inhibiting PHD1, but not PHD2 or PHD3, blocked the activation of p53 to enhance the response to multiple chemotherapeutic agents. In determining the molecular mechanisms that aid chemotherapy resistance, researchers have uncovered a new component in the role of PHD1 in cancer development.

"We demonstrated that PHD1 can affect the way colorectal cancer responds to the three most common chemotherapeutic drugs used to treat CRC today,” said researcher Sofie Deschoemaeker. “By blocking PHD1, we rob CRC cells of their ability to harness p53 to the cell-repair yoke, even when this protein is mutated (as often occurs in CRC). That means the CRC cells are exposed to the full DNA damage caused by these genotoxic drugs, resulting in greater cell death and thus a better response to the chemotherapy and, ultimately, an improved outcome."