Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes

• Published in: Cell death & disease 2021-11, Vol.12 (11), p.1075-1075, Article 1075
• Main Authors: Davidson, Kathryn, Grevitt, Paul, Contreras-Gerenas, Maria F., Bridge, Katherine S., Hermida, Miguel, Shah, Kunal M., Mardakheh, Faraz K., Stubbs, Mark, Burke, Rosemary, Casado, Pedro, Cutillas, Pedro R., Martin, Sarah A., Sharp, Tyson V.
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/51; 13/89; 42/41; 42/89; 631/67/1059/602; 631/67/1612/1350; 64/60; 82/58; 82/80; Animals; Antibodies; Apoptosis; Biochemistry; Biomarkers; Biomedical and Life Sciences; Cancer therapies; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell Culture; Cell cycle; Cell death; CRISPR; Female; Genes; Humans; Immunology; Immunotherapy; Intracellular Signaling Peptides and Proteins - deficiency; Lethality; Libraries; Life Sciences; LIM Domain Proteins - deficiency; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical prognosis; Medical research; Mice; Mice, Inbred NOD; Mutation; Non-small cell lung carcinoma; Patients; Proof of Concept Study; Proteins; Small cell lung carcinoma; Therapeutic targets; Transfection; Tumor suppressor genes; Tumorigenesis; Tumors; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04355-7

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1 −/− tumours in subcutaneous xenograft models, with no significant effect in LIMD1 +/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.