Validating novel synthetically lethal vulnerabilities in lung cancer

"LIMD1 (LIM domains containing 1) is a tumour suppressor gene frequently lost during the early stages of non-small cell lung cancer (NSCLC), resulting in a worse outcome for LIMD1-deficient patients.
LIMD1 deficiency is present in approximately fifty percent of NSCLC cases, representing at least 21,000 patients in the United Kingdom and 1.2 million worldwide. Our lab, in collaboration with the CRUK Functional Genomic Centre, conducted a whole genome CRISPR-Cas9 functional genomic screen to identify novel vulnerabilities in LIMD1-deficient lung cancer cells in order to develop personalised treatments for this subset of NSCLC patients.
In LIMD1-deficient cells, the screen revealed a significant enrichment of genes involved in selenocysteinyl-tRNA biosynthesis and selenocysteine incorporation as novel dependencies. Notably, the only enzyme identified to contain selenocysteine was GPX4, which detoxifies lipid peroxides and protects cells from ferroptosis. We therefore hypothesise that early LIMD1 loss may influence lung cancer cell sensitivity or resistance to ferroptosis.
Our goals include validating GPX4 as a novel vulnerability in LIMD1-deficient lung cancer cells, assessing sensitivity or resistance to ferroptosis in a larger panel of lung cancer cell lines, and elucidating the mechanisms that regulate sensitivity or resistance to ferroptosis in LIMD1-deficient cells. Using a siRNA-mediated method to reduce GPX4 levels, our findings indicate that LIMD1-deficient cells are more sensitive than LIMD1-proficient cells. In addition, when treated with ferroptosis-inducing compounds RSL3 and erastin, LIMD1-deficient cells were more sensitive than LIMD1-sufficient cells.
Our lab is exploring the unrealised potential of LIMD1 in the biology of lung cancer, and we hope this will lead to revolutionary advances in targeted cancer treatments for a significant subset of patients."