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

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

doi:10.18632/oncotarget.27961

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.

Highlights

Metastatic cutaneous apocrine gland carcinoma (CAC) is an extreme rare malignancy arising from a sweat gland with < 30 reported cases in the literature [1,2,3]
Partner and localizer of BRCA2 (PALB2) is a tumor suppressor gene which encodes a protein that stabilizes BRCA2 and allows to scaffold the molecular BRCA1PALB2-BRCA2 complex at double-stranded breaks (DSBs) to prevent cells from accumulating DNA damage [21]. It plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathway, loss of which is a defining feature of the BRCAness phenotype and is associated with increased sensitivity to DNA damaging agents and poly-(ADP)-ribose polymerase inhibitors (PARPis) [22]
To evaluate if the efficacy of BETi and PARPi correlated in cancer cells with PALB2 alterations, we examined the efficacy of BETi JQ1 and two poly ADP ribose polymerase (PARP) inhibitors olaparib and talazoparib across 43 PALB2 altered 763 non-altered human cancer cell lines [25] with overlapping drug response data available from www.oncotarget.com

Summary

Introduction

Metastatic cutaneous apocrine gland carcinoma (CAC) is an extreme rare malignancy arising from a sweat gland with < 30 reported cases in the literature [1,2,3] Majority of these reported cases are derived from the axilla with only a few cases originating from other regions of the integumentary system [4]. The tumorigenesis of these rare cancers is largely unclear, but histologically cutaneous apocrine gland carcinomas mimic metastatic apocrine breast cancer or apocrine carcinomas arising in ectopic breast tissue [5, 6]. There is a need for better understanding of the complex biology of cutaneous apocrine sweat gland carcinomas, including the molecular and genetic background of these malignancies to develop rationales for therapeutic strategies

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