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, y...

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Autores principales: Kathryn Davidson, Paul Grevitt, Maria F. Contreras-Gerenas, Katherine S. Bridge, Miguel Hermida, Kunal M. Shah, Faraz K. Mardakheh, Mark Stubbs, Rosemary Burke, Pedro Casado, Pedro R. Cutillas, Sarah A. Martin, Tyson V. Sharp
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Publicado: Nature Publishing Group 2021
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spelling oai:doaj.org-article:006a5cc989ef440e83fa93a4ded657082021-11-14T12:06:54ZTargeted therapy for LIMD1-deficient non-small cell lung cancer subtypes10.1038/s41419-021-04355-72041-4889https://doaj.org/article/006a5cc989ef440e83fa93a4ded657082021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04355-7https://doaj.org/toc/2041-4889Abstract 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.Kathryn DavidsonPaul GrevittMaria F. Contreras-GerenasKatherine S. BridgeMiguel HermidaKunal M. ShahFaraz K. MardakhehMark StubbsRosemary BurkePedro CasadoPedro R. CutillasSarah A. MartinTyson V. SharpNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-10 (2021)
institution DOAJ
collection DOAJ
language EN
topic Cytology
QH573-671
spellingShingle Cytology
QH573-671
Kathryn Davidson
Paul Grevitt
Maria F. Contreras-Gerenas
Katherine S. Bridge
Miguel Hermida
Kunal M. Shah
Faraz K. Mardakheh
Mark Stubbs
Rosemary Burke
Pedro Casado
Pedro R. Cutillas
Sarah A. Martin
Tyson V. Sharp
Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes
description 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.
format article
author Kathryn Davidson
Paul Grevitt
Maria F. Contreras-Gerenas
Katherine S. Bridge
Miguel Hermida
Kunal M. Shah
Faraz K. Mardakheh
Mark Stubbs
Rosemary Burke
Pedro Casado
Pedro R. Cutillas
Sarah A. Martin
Tyson V. Sharp
author_facet Kathryn Davidson
Paul Grevitt
Maria F. Contreras-Gerenas
Katherine S. Bridge
Miguel Hermida
Kunal M. Shah
Faraz K. Mardakheh
Mark Stubbs
Rosemary Burke
Pedro Casado
Pedro R. Cutillas
Sarah A. Martin
Tyson V. Sharp
author_sort Kathryn Davidson
title Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes
title_short Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes
title_full Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes
title_fullStr Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes
title_full_unstemmed Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes
title_sort targeted therapy for limd1-deficient non-small cell lung cancer subtypes
publisher Nature Publishing Group
publishDate 2021
url https://doaj.org/article/006a5cc989ef440e83fa93a4ded65708
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