Title: Uncovering the mechanism of resistance to RNA-incorporating drugs in cancer
Funder: The Academy of Medical Sciences

Abstract: Nucleoside analogue drugs such as 5-Fluorouracil (5-FU) and gemcitabine are common components of chemotherapeutic regimens used in treating cancers of the pancreas, bowel, and breast. However, drug-resistance remains a critical limitation to their clinical application, highlighting an urgent and unmet need for a better understanding of mechanisms of cellular response to these agents to improve treatment outcome. The incorporation of 5-FU into RNA, leading to production of aberrant mRNAs, underpins its anti-cancer efficacy. Cancer cells also exhibit augmented oxidative stress which damages mRNAs. Translation of aberrant or damaged mRNAs results in ribosome stalling and production of truncated proteins or protein aggregates with cytotoxic effects. The Ribosome Quality-Control (RQC) mechanism detects aberrant mRNAs and degrades their nascent peptides, thus preventing their cytotoxic consequences. However, despite substantial progress in our understanding of the mechanism of RQC, very little information is available about the importance of RQC in cancer, where aberrant mRNAs are abundant due to stress, drug treatments, and abnormal mRNA processing. My preliminary data indicate that RQC plays a key role in cancer cells’ growth and their resistance to 5-FU. Thus, I hypothesise that optimal RQC performance is essential for cancer cells’ survival and their resistance to RNA-incorporating drugs such as 5-FU. This project aims to assess the effects of RQC-depletion on tumourigenesis and 5-FU-resistance. Besides providing ground-breaking insights into the mechanisms of tumourigenesis and drug-resistance, this work will also be critical in evaluating the potential benefits of targeting RQC to enhance the efficacy of 5-FU and other RNA-incorporating drugs.

Lay abstract: Of more than 10,000 individuals that are diagnosed with pancreatic cancer in the UK each year, only 7% survive longer than 5 years. Currently, limited options are available for treatment of pancreatic cancer and resistance to therapy is very common. The dismal prognosis of pancreatic cancer and the stale therapies used highlight an urgent need for innovative approaches to improve patients’ outcomes. Production of defective proteins, which are abundant in cancer (particularly following chemotherapy), can harm the cells. Therefore, our cells use a Quality Control process called RQC that prohibits the production of faulty proteins, thereby avoiding their harmful consequences. However, our knowledge of the importance of RQC in cancer and resistance to chemotherapy is very limited. I have evidence that suggest the optimal RQC performance is essential for resistance of pancreatic cancer cells to specific chemotherapeutic drugs that cause production of defective proteins. Hence, I propose that reliance of cancer cells on RQC to resist to chemotherapeutic treatments is an exploitable weakness of cancers that can be used for development of novel and effective anti-cancer treatments. This study aims to define the role of RQC in pancreatic cancer and investigate if blocking the activity of RQC will enhance the efficacy of chemotherapy treatments in pancreatic cancer. I anticipate that this study will change our understanding of the fundamental biology of resistance of pancreatic cancers to chemotherapy treatments. These findings could also potentially be used to develop new forms of treatment for pancreatic and likely many other types of cancer.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS