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

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.

A Highly Sensitive and Specific Non‐Invasive Test through Genome‐Wide 5‐Hydroxymethylation Mapping for Early Detection of Lung Cancer

“…[ 37 ] Of note, ≈ 45% of NSCLC are deficient in LIMD1 , making it a potential therapeutic target. [ 38 ] In addition, the normalized RNA‐seq data of 514 primary tumors and 59 normal tissues were collected from the TCGA LUAD dataset for 98 of the 105 final model component genes. Differential analysis revealed that 72 (73.5%) of these 98 model genes were differently expressed between tumors and normal tissues (Figure 6E), showing the relevance of these 5hmC markers in cfDNA that reflects tumor transcriptional dysregulation in an independent collection of lung cancer patients.…”

“…[36] Another marker gene, LIMD1 (encoding LIM Domain Containing 1; Figure 6D), was a tumor suppressor that showed reduced expression in lung cancers. [37] Of note, ≈ 45% of NSCLC are deficient in LIMD1, making it a potential therapeutic target. [38] In addition, the normalized RNA-seq data of 514 primary tumors and 59 normal tissues were collected from the TCGA LUAD dataset for 98 of the 105 final model component genes.…”

Statin Treatment as a Targeted Therapy for APC-Mutated Colorectal Cancer

“…To overcome this, the concept of exploiting synthetic lethal relationships for cancer treatment has been proposed as an approach to the targeting of tumor suppressor loss ( 19 , 20 ). Indeed, we have recently shown that this is a successful approach for the targeting of other non-enzymatic tumor suppressor gene scaffold proteins such as LIMD1 ( 21 ). Two genes are said to be synthetically lethal if loss of either gene alone is compatible with viability, but loss of both causes cell death.…”