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Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010 Page 289

Carboplatin resistance
Our previous data indicated the relevance of dysregulated plasma miR-146a in different breast cancer subtypes,
suggesting its potential role in breast cancer biology and tumor progression . Wilczyński et al. compared
[140]
[139]
miR-146a expression levels in primary tumors and omental metastases of 48 patients who had undergone
surgery of advanced ovarian serous cancer. The miR-146a levels in primary tumors were elevated compared
with normal ovary tissues and metastases. There was a negative correlation between miR-146a expression
in primary tumors and serum amounts of cancer antigen 125 (CA125). Decreased miR-146a expression was
associated with a shorter overall and progression-free survival, most notably with carboplatin resistance of
metastases.

Using real-time qPCR miRNA OpenArrays, Benson et al. measured miRNA concentrations in plasma
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samples from 14 patients with platinum-resistant, recurrent ovarian cancer enrolled in a phase II clinical trial
that were treated with a low dose of the hypomethylating agent decitabine followed by carboplatin. Ten miRNAs
(miR-193a-5p, miR-375, miR-339-3p, miR-340-5p, miR-532-3p, miR-133a-3p, miR-25-3p, miR-10a-5p, miR-616-5p
and miR-148b-5p) displayed multi-fold changes in concentrations in recurrent platinum resistant ovarian
cancer patients that were associated with a response to decitabine followed by carboplatin chemotherapy.
In addition, circulating miR-148b-5p concentrations were associated with progression-free survival and
may represent a novel biomarker for therapeutic response to this chemotherapy regimen in patients with
recurrent, drug-resistant ovarian cancer.

Cis- and carboplatin resistance
MiRNA can be released by apoptotic and necrotic cells into the blood circulation, but they can also be
actively secreted in extracellular vesicles (EVs). EVs are thought to play an important role in cell-to-cell
communication . In this regard, Kuhlmann et al. designed an integrated NGS-based workflow for
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[143]
analyzing the signature of EV-associated miRNAs in the plasma of platinum-resistant ovarian cancer
patients. They found a panel of EV-associated miRNAs, such as miR-181a, miR-1908, miR-21, miR-486 and
miR-223, which were differentially abundant in the plasma of platinum-resistant patients.

BRCA1 and BRCA2 play an important role in the homologous recombination DNA repair system. Cells
harboring mutations of BRCA1/BRCA2 are especially sensitive to platinum . Furthermore, the Ku heterodimer
[144]
consisting of two subunits (Ku70 and Ku80) plays a central role as an initial DNA end binding factor in the
classical non-homologous end joining pathway . Choi et al. detected a resistance mechanism by which
[145]
[146]
miR-622 induced cis- and carboplatin resistance in BRCA1 mutant high-grade serous ovarian carcinomas by
targeting the Ku complex and restoring homologous recombination mediated double strand break repair. MiR-
622 inversely correlated with Ku expression during the cell cycle, suppressed non-homologous end-joining, but
facilitated homologous recombination mediated double strand break repair in the S phase. Notably, a high
expression of miR-622 in BRCA1-deficient high-grade serous ovarian carcinomas correlated with worse
outcome after platinum chemotherapy.

CONCLUSION
Despite recent advances in treatment regimens, ovarian cancer remains one of the most deadly diseases
because of its development of drug resistance. Due to the high number of relapsed ovarian cancer patients,
new therapy options for platinum resistant disease are needed. The cytotoxicity of platinum is based on the
formation of DNA adducts, including DNA-protein cross-links, DNA monoadducts and interstrand DNA
cross-links, activating DNA damage and consequently, the cell death pathway. However, the events leading
to platinum resistance are not well understood. Besides genetic alterations, changes in epigenetic regulation
may contribute to this resistance. In particular, epigenetically silenced tumor suppressor genes involved in
apoptosis, DNA repair and the cell cycle may be the main reasons for drug resistance. As shown by previous
studies and described above, among other factors, BRCA1, BRCA2, MLH1, p53 and p21 contribute to platinum
resistance via DNA damage and repair, while p21, RASSF1, Bax and p53 contribute via apoptosis. The most