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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04355-7 |
| _version_ | 1798034891911200768 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T20:49:42Z |
| format | Article |
| id | doaj.art-006a5cc989ef440e83fa93a4ded65708 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T20:49:42Z |
| publishDate | 2021-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-006a5cc989ef440e83fa93a4ded657082022-12-22T04:03:52ZengNature Publishing GroupCell Death and Disease2041-48892021-11-01121111010.1038/s41419-021-04355-7Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypesKathryn Davidson0Paul Grevitt1Maria F. Contreras-Gerenas2Katherine S. Bridge3Miguel Hermida4Kunal M. Shah5Faraz K. Mardakheh6Mark Stubbs7Rosemary Burke8Pedro Casado9Pedro R. Cutillas10Sarah A. Martin11Tyson V. Sharp12Barts Cancer Institute, Queen Mary University of London, John Vane Science CentreBarts Cancer Institute, Queen Mary University of London, John Vane Science CentreBarts Cancer Institute, Queen Mary University of London, John Vane Science CentreYork Biomedical Research Institute, University of YorkDepartment of Bioengineering, Imperial CollegeBarts Cancer Institute, Queen Mary University of London, John Vane Science CentreBarts Cancer Institute, Queen Mary University of London, John Vane Science CentreCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer ResearchCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer ResearchBarts Cancer Institute, Queen Mary University of London, John Vane Science CentreBarts Cancer Institute, Queen Mary University of London, John Vane Science CentreBarts Cancer Institute, Queen Mary University of London, John Vane Science CentreBarts Cancer Institute, Queen Mary University of London, John Vane Science CentreAbstract 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.https://doi.org/10.1038/s41419-021-04355-7 |
| spellingShingle | 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 Cell Death and Disease |
| title | 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_short | Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes |
| title_sort | targeted therapy for limd1 deficient non small cell lung cancer subtypes |
| url | https://doi.org/10.1038/s41419-021-04355-7 |
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