Davidson, Kathryn, Grevitt, Paul, Contreras-Gerenas, Maria F et al. (10 more authors) (2021) Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes. Cell Death and Disease. p. 1075. ISSN 2041-4889
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021. The Author(s). |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 19 Nov 2021 11:00 |
Last Modified: | 27 Nov 2024 00:41 |
Published Version: | https://doi.org/10.1038/s41419-021-04355-7 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41419-021-04355-7 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:180653 |