Despite targeted treatments for cancer, chemoresistance— the tendency to evade or resist therapeutics is on the rise. Chemoresistant cancer cells can overcome, reverse or bypass the effects of therapeutic agents, thereby, deeming them ineffective. A study by researchers from the National Institute of Immunology, New Delhi sheds novel insights into how protein interactions trigger chemoresistance in cancer cells and how disrupting such interactions can help improve the therapeutic outcomes of existing treatments.

Normal cells use DNA repair mechanisms to help correct any errors in the DNA sequence. However, cancer cells take advantage of the same mechanisms to counter the effects of ‘genotoxic’ or DNA-damaging agents used widely in the treatment of various cancers. As these cells continue repairing the damaged DNA, they become increasingly resistant to the DNA-damaging agents. Such resilient cells are often a cause of recurrent and aggressive cancers.

Chromatin remodelling or the rearrangement of DNA-protein complexes is a crucial step in DNA repair that enables repair enzymes to access the damaged region. Dr. Sagar Sengupta, Director at the National Institute of Biomedical Genomics, Kolkata, and a Staff Scientist VII (deputation) at NII, and his team have previously shown how BLM and RAD54, two pivotal proteins involved in DNA damage-sensing and repair also interact and mediate dynamic changes in the chromatin. Further, BLM enhances RAD54-mediated chromatin remodelling, thus, improving the efficiency of a key DNA repair pathway.

In their current work published in the Journal of Clinical Investigation, the researchers uncovered mechanisms by which the BLM-RAD54 interaction induces chemoresistance in colon cancer. Furthermore, they identified drug candidates that can improve treatment sensitivity and response. Ritu Agrawal, a first author of the paper, (former PhD student and current research associate in Sengupta’s lab), says, “We set out to investigate whether disrupting the BLM-RAD54 interaction could resensitize drug-resistant cancer cells to chemotherapeutic agents.”

The researchers found that a 32 amino acid-long stretch in the BLM protein was indispensable to the BLM-RAD54 interaction. This sequence enhanced the chromatin remodelling activity of RAD54, as well as DNA repair responses in colon cancer cells. Cells exposed to the BLM peptide showed accelerated growth and were also resistant to commonly used chemotherapeutic agents such as camptothecin, cisplatin and oxaliplatin, compared to cells where BLM expression was abolished.

Delving deeper into the mechanisms that confer BLM-induced drug resistance, the researchers found that BLM and RAD54 were indeed, partners in crime. Not only were the two proteins present at the promoter regions of multiple MDR (multiple drug resistance) genes, but they also enhanced MDR gene expression. Moreover, BLM-RAD54-induced chemoresistant cells were aggressively malignant and formed larger tumours in mice, even in the presence of chemotherapeutic drugs.

Next, the researchers examined whether disrupting the BLM-RAD54 partnership would resensitise chemoresistant colon cancer cells. Upon extensively screening 1280 FDA/European Medical Agencies-approved small molecules, they found that 17 molecules disrupted at least 70% of the BLM-RD54 interaction. Of these, three molecules specifically reduced chemoresistance in cells exposed to the BLM peptide.

Finally, a combined treatment of the specific chemotherapeutic agent and the newly identified small drug molecules inhibited tumor growth in mice injected with chemoresistant colon cancer cells. Agrawal further noted, “These molecules have been FDA-approved and have shown effectiveness in a syngeneic mouse model system (where tumour cells derived from one mouse are transplanted into another with identical genetic background). They can be used in combination with existing anti-cancer therapies to improve their efficacy by reducing chemoresistance. Ongoing clinical trials will help establish their therapeutic value in colon cancer patients”.

Cancer has become alarmingly prevalent, and its treatment itself is debilitating and draining– physically, mentally, and financially. Adjunct therapies that can help prevent its recurrence and improve initial treatment response by reducing drug resistance are the need of the hour. These findings can potentially translate into effective treatments for patients battling drug-resistant cancer.