Abstract
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.
Highlights
Lung cancer remains the most common cancer in the Western world with ~2 million cases reported worldwide each year [1]
From our compound library screen, we identified a multi-kinase checkpoint kinase 1 (Chk1) inhibition inhibitor, PF-477736 that selectively kills LIMD1-negative cells PF-477736 was originally developed for use in combination compared to LIMD1-proficient cells
Whilst this inhibitor was therapy with DNA damage-inducing agents as a sub-nanomolar designed as a checkpoint kinase 1 (Chk1) inhibitor, we have shown that Chk1 inhibition does not confer the synthetic lethal
Summary
Lung cancer remains the most common cancer in the Western world with ~2 million cases reported worldwide each year [1]. To test PF-477736 in nontransformed lung cells, we generated LIMD1−/− small airway epithelial cells (SAEC) that had been immortalised by overexpressing Bmi (SAEC-Bmi1) These SAEC are a mixture of both type I and type II alveolar cells, thereby serving as an appropriate model of LUAD progenitor cells, which have been CRISPR-Cas edited to express a N-terminal truncated form of LIMD1 in significantly lower levels compared to non-targeting controls, thereby representing an in vitro model of LIMD1 loss in the development of adenocarcinoma (Fig. 4A). We have identified that PF-477736 selectively induces apoptosis in LIMD1−/− cells by targeting multiple susceptibility pathways, whilst sparing LIMD1+/+ cells This is the first evidence supporting a targeted therapeutic approach for the treatment of lung cancers with reduced or loss of LIMD1 expression
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