Small molecules that disrupt RAD54-BLM interaction hamper tumor proliferation in colon cancer chemoresistance models

Layman Abstract

One of the biggest problems of cancer is its recurrence and metastasis. Recurrence happens when the individual develops resistance to the anti-cancer drugs the person is being treated with. Many times the anti-cancer drugs become ineffective as they either cannot enter into the cancer cells and kill it or machineries within the cancer cells which work overtime to  remove the drug from within the cancer cells, thereby rendering it ineffective.

The present work has addressed the mechanism of how cancer chemoresistance occur in the cancer cells at the genomic level and how disrupting that mechanism can again make the anti-cancer drug more effective. Taking colon cancer as the model system the authors show that role of two proteins RAD54 and BLM in this process. RAD54 has the capability to make the genome more loosely bound (technically called chromatin remodelling) and thereby helps in activation of genes. BLM helps RAD54 in this process. In this publication the authors show that RAD54-BLM complex can enhance the activation of genes involved in removing the anti-cancer drugs from within the cancer cells – and is thereby a very important reason for the development of chemoresistance.

In the second part of the work the authors identify three small molecules (by physically screening a large library of such molecules) which disrupt RAD54-BLM interaction within the cells. Hence the presence of these three small molecules allow the grontline anti-cancer drugs to remain within the cancer cells and become effective for a longer time. The author provide evidence regarding the effect of the three small molecules not only in cells which had been made resistant in a petridish but also in multiple animal models. Mice treated with such drugs show little or no tumour progression.

Since these drugs have already been approved by the regulatory authorities – they can be used in combination with the frontline chemotherapeutic drugs (technically referred as adjunct therapy) in the treatment of colon cancer.

Scientific abstract

RAD54 and BLM helicase play pivotal roles during homologous recombination repair (HRR) ensuring genome maintenance. BLM amino acids (181-212) interacts with RAD54 and enhances its chromatin remodelling activity. Functionally, this interaction heightens HRR, leading to a decrease in residual DNA damage in colon cancer cells. This contributes to chemoresistance in colon cancer cells against cisplatin, camptothecin and oxaliplatin, eventually promoting tumorigenesis in preclinical colon cancer mouse models. ChIP-seq analysis and validation revealed increased BLM/RAD54 co-recruitment on MRP2 promoter in camptothecin resistant colon cancer cells, leading to BLM-dependent enhancement of RAD54-mediated chromatin remodelling. We screened Prestwick small molecule library intending to revert camptothecin and oxaliplatin induced chemoresistance by disrupting BLM-RAD54 interaction. Three FDA/EMA approved candidates were identified which could disrupt this interaction. These drugs bind to RAD54, alter its conformation and abrogate BLM-RAD54 dependent chromatin remodeling on G5E4 and MRP2 arrays. Notably, the small molecules also reduced HRR repair efficiency in resistant lines, diminished anchorage independent growth, hampered the proliferation of tumors generated using camptothecin and oxaliplatin resistant colon cancer cells in both xenograft and syngeneic mouse models in BLM dependent manner. Hence the three identified small molecules can serve as possible viable candidates for adjunct therapy in colon cancer.

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