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Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma
Cutaneous apocrine carcinoma is an extreme rare malignancy derived from a sweat gland. Histologically sweat gland cancers resemble metastatic mammary apocrine carcinomas, but the genetic landscape remains poorly understood. Here, we report a rare metastatic case with a PALB2 aberration identified pr...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169071/ https://www.ncbi.nlm.nih.gov/pubmed/34084283 http://dx.doi.org/10.18632/oncotarget.27961 |
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author | Mäkelä, Rami Härmä, Ville Badra Fajardo, Nibal Wells, Greg Lygerou, Zoi Sangfelt, Olle Kononen, Juha Rantala, Juha K. |
author_facet | Mäkelä, Rami Härmä, Ville Badra Fajardo, Nibal Wells, Greg Lygerou, Zoi Sangfelt, Olle Kononen, Juha Rantala, Juha K. |
author_sort | Mäkelä, Rami |
collection | PubMed |
description | Cutaneous apocrine carcinoma is an extreme rare malignancy derived from a sweat gland. Histologically sweat gland cancers resemble metastatic mammary apocrine carcinomas, but the genetic landscape remains poorly understood. Here, we report a rare metastatic case with a PALB2 aberration identified previously as a familial susceptibility gene for breast cancer in the Finnish population. As PALB2 exhibits functions in the BRCA1/2-RAD51-dependent homologous DNA recombination repair pathway, we sought to use ex vivo functional screening to explore sensitivity of the tumor cells to therapeutic targeting of DNA repair. Drug screening suggested sensitivity of the PALB2 deficient cells to BET-bromodomain inhibition, and modest sensitivity to DNA-PKi, ATRi, WEE1i and PARPi. A phenotypic RNAi screen of 300 DNA repair genes was undertaken to assess DNA repair targeting in more detail. Core members of the HR and MMEJ pathways were identified to be essential for viability of the cells. RNAi inhibition of RAD52-dependent HR on the other hand potentiated the efficacy of a novel BETi ODM-207. Together these results describe the first ever CAC case with a BRCAness genetic background, evaluate combinatorial DNA repair targeting, and provide a data resource for further analyses of DNA repair targeting in PALB2 deficient cancers. |
format | Online Article Text |
id | pubmed-8169071 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-81690712021-06-02 Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma Mäkelä, Rami Härmä, Ville Badra Fajardo, Nibal Wells, Greg Lygerou, Zoi Sangfelt, Olle Kononen, Juha Rantala, Juha K. Oncotarget Research Paper Cutaneous apocrine carcinoma is an extreme rare malignancy derived from a sweat gland. Histologically sweat gland cancers resemble metastatic mammary apocrine carcinomas, but the genetic landscape remains poorly understood. Here, we report a rare metastatic case with a PALB2 aberration identified previously as a familial susceptibility gene for breast cancer in the Finnish population. As PALB2 exhibits functions in the BRCA1/2-RAD51-dependent homologous DNA recombination repair pathway, we sought to use ex vivo functional screening to explore sensitivity of the tumor cells to therapeutic targeting of DNA repair. Drug screening suggested sensitivity of the PALB2 deficient cells to BET-bromodomain inhibition, and modest sensitivity to DNA-PKi, ATRi, WEE1i and PARPi. A phenotypic RNAi screen of 300 DNA repair genes was undertaken to assess DNA repair targeting in more detail. Core members of the HR and MMEJ pathways were identified to be essential for viability of the cells. RNAi inhibition of RAD52-dependent HR on the other hand potentiated the efficacy of a novel BETi ODM-207. Together these results describe the first ever CAC case with a BRCAness genetic background, evaluate combinatorial DNA repair targeting, and provide a data resource for further analyses of DNA repair targeting in PALB2 deficient cancers. Impact Journals LLC 2021-05-25 /pmc/articles/PMC8169071/ /pubmed/34084283 http://dx.doi.org/10.18632/oncotarget.27961 Text en Copyright: © 2021 Mäkelä et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Mäkelä, Rami Härmä, Ville Badra Fajardo, Nibal Wells, Greg Lygerou, Zoi Sangfelt, Olle Kononen, Juha Rantala, Juha K. Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma |
title |
Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma
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title_full |
Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma
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title_fullStr |
Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma
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title_full_unstemmed |
Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma
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title_short |
Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma
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title_sort | ex vivo analysis of dna repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169071/ https://www.ncbi.nlm.nih.gov/pubmed/34084283 http://dx.doi.org/10.18632/oncotarget.27961 |
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