Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes: a Proof-of-Concept synthetic lethal study

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 binds multiple binding partners to suppress tumourigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD11, 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 synthetic lethal compounds with LIMD1 loss in lung cancer 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 is effective in treating LIMD1-/- tumors in subcutaneous xenograft models, with no significant effect in LIMD1+/+ cells. We have identified a novel drug tool with significant preclinical characterization that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Hela Cell

DISEASE(S): Cervix Carcinoma

SUBMITTER: Pedro Casado-Izquierdo  

LAB HEAD: Pedro R. Cutillas

PROVIDER: PXD023674 | Pride | 2022-02-16

REPOSITORIES: Pride