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Research Papers:

Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma

Rami Mäkelä, Ville Härmä, Nibal Badra Fajardo, Greg Wells, Zoi Lygerou, Olle Sangfelt, Juha Kononen and Juha K. Rantala _

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Oncotarget. 2021; 12:1100-1109. https://doi.org/10.18632/oncotarget.27961

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Abstract

Rami Mäkelä1, Ville Härmä1,2, Nibal Badra Fajardo3, Greg Wells2, Zoi Lygerou3, Olle Sangfelt4, Juha Kononen5 and Juha K. Rantala1,2

1 Misvik Biology Oy, Turku, Finland

2 University of Sheffield, Department of Oncology and Metabolism, Sheffield, UK

3 University of Patras, Laboratory of General Biology, Patras, Greece

4 Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm, Sweden

5 Docrates Cancer Hospital, Helsinki, Finland

Correspondence to:

Juha K. Rantala,email: rantala@misvik.com

Keywords: cutaneous apocrine sweat gland carcinoma; ex vivo drug screening; DNA repair; PALB2; rare cancer

Received: July 30, 2020     Accepted: May 03, 2021     Published: May 25, 2021

Copyright: © 2021 Mäkelä et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

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.


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