Drug resistance in ovarian cancer: from mechanism to clinical trial

Abstract

Ovarian cancer is the leading cause of gynecological cancer-related death. Drug resistance is the bottleneck in ovarian cancer treatment. The increasing use of novel drugs in clinical practice poses challenges for the treatment of drug-resistant ovarian cancer. Continuing to classify drug resistance according to drug type without understanding the underlying mechanisms is unsuitable for current clinical practice. We reviewed the literature regarding various drug resistance mechanisms in ovarian cancer and found that the main resistance mechanisms are as follows: abnormalities in transmembrane transport, alterations in DNA damage repair, dysregulation of cancer-associated signaling pathways, and epigenetic modifications. DNA methylation, histone modifications and noncoding RNA activity, three key classes of epigenetic modifications, constitute pivotal mechanisms of drug resistance. One drug can have multiple resistance mechanisms. Moreover, common chemotherapies and targeted drugs may have cross (overlapping) resistance mechanisms. MicroRNAs (miRNAs) can interfere with and thus regulate the abovementioned pathways. A subclass of miRNAs, "epi-miRNAs", can modulate epigenetic regulators to impact therapeutic responses. Thus, we also reviewed the regulatory influence of miRNAs on resistance mechanisms. Moreover, we summarized recent phase I/II clinical trials of novel drugs for ovarian cancer based on the abovementioned resistance mechanisms. A multitude of new therapies are under evaluation, and the preliminary results are encouraging. This review provides new insight into the classification of drug resistance mechanisms in ovarian cancer and may facilitate in the successful treatment of resistant ovarian cancer.

Keywords: Clinical trials; Ovarian cancer; Resistance mechanisms; miRNAs.

Fig. 1

The summery of miRNA-mediated resistance mechanisms (a) Abnormal transmembrane transport; (b) Alterations of DNA damage repair; (c) Dysregulation of cancer-associated signal pathway; (d) Epigenetic modification

Fig. 2

Abnormal transmembrane transport. The SLC31A1, SLC22A1/2/3, as members of SLC superfamily, are significant transporters in charge of drug inflow. Downregulation of SLC transporters reduce platinum uptake, leading to chemoresistance in ovarian cancer. The role of miRNA in SLC expression lacks sufficient evidence. The ABC transporter family include ABCB1, ABCG2, ABCC1, which are responsible for drug efflux and then reduce intracellular concentration of platinum. miR130a/b, miR-186, miR-495 can directly bind with the 3'-UTR of ABCB1 mRNA or regulate PTEN, XIPA, and PI3K, leading to decreased ABCB1 transcription or translation level. miR-21-5p and miR-212-3p also have a regulatory factor of ABCB1 and ABCG2, respectively. miR-185-5p, miR-326, miR-508-3p and miR-134 can regulate the expression of ABCC1. ATP7A/7B are another contributor of drug efflux. miR-139 can directly bind to the 3'-UTR of ATP7A/7B, leading to apoptosis induction and increasing the chemosensitivity of ovarian cancer. MT can bind to cisplatin and deactivates it, which decreases drug efficacy and induces drug resistance. GST catalyzes glutathione to bind platinum and causes drug inactivation, which is associated with platinum resistance in ovarian cancer. (SLC, solute carrier superfamily; GST, Glutathione transferase; MT, Metallothionein)

Fig. 3

Alterations of DNA damage repair. DDR generally consists of HRR, NHEJ, Replication fork, BER, NER, MMR, TLS, and FA. The repair of DSBs occurs predominately through NHEJ repair pathway in conjunction with HRR pathway. NHEJ are initiated by binding of Ku70–Ku80 heterodimer to DNA ends. The subsequent recruitment and autophosphorylation of DNA-PKcs bring the DNA ends together and allow their ligation by XRCC4–LIG4. MRN complex (MRE11-RAD50-NBS1), an important repair factor of HRR, detects the DNA damage firstly and activates downstream signaling. Besides, it exerts nuclease activity to resect DNA end, guiding to HRR. Further, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Decreased DYNLL1 restores HR-mediated double-strand DNA breaks repair. Replication fork protection is a modality independent of DSBs, which contributes to gene stabilization, leading to chemoresistance and PARPi resistance. Additionally, down-expression of 53BP1 protein is another mechanism to restore DNA end resection. Shieldin (SHLD1, SHLD2, SHLD3 and REV7), as an effector complex of 53BP1, can mediate 53BP1 dependent DNA repair in a BRCA-independent manner. The kinases ATR and ATM have crucial roles in DDR pathway, such as maintaining replication fork stability and regulating CHK1 and CHK2.CHK1 can activate the G2/M inhibiting kinase WEE1 to maintain genomic integrity. Some miRNAs were shown to regulate the expression of components involved in HRR, NHEJ, Replication fork protection, TLS, and FA, but the interaction between miRNA and BER/ NER/ MMR lack sufficient evidence. (SLC, solute carrier superfamily; GST, Glutathione transferase; MT, Metallothionein)

Fig. 4

Dysregulation of cancer-associated signal pathway. A series of signal pathways collectively regulates the biological process in human malignancies, which is associated with the proliferation, invasion and therapeutic resistance. The signaling pathways mainly include NFκB, PI3K/Akt, JAK/STAT, Notch, GAS6/AXL, TGF-β, MAPK, Hippo/YAP patwhay. Some miRNAs have ability to regulate the key members of these mentioned pathway, including JAK/STAT, GAS/AXL, MAPK, PI3K/Akt, NFκB,, TGF-β, Hippo/YAP, but there are no investigations about the interaction between miRNAs and Notch in ovarian cancer. The dysregulated cancer-associated signal pathway interfere with apoptosis, cell cycle, and immune status, resulting in multidrug resistance. Molecule targets in these pathway may provide a new approach for drug resistance in OC. The γ-secretase inhibitor DAPT, c-Myc targeting small molecule JQ1, an inhibitor of NFκB DHMEQ suppress the proliferation and induce apoptosis to reversing drug resistance in OC. (JQ1, novel cell-permeable small molecule; BAD, Bcl-2 antagonist of death; IKKα, inhibitor of nuclear factor-κB subunit-α; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; DHMEQ, Dehydroxymethylepoxyquinomicin; MDSCs, Myeloid-derived suppressor cells; CSCs, cancer stem cells;BEZ235,a dual PI3K/mTOR inhibitor; DAPT, γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester)

Fig. 5

Epigenetic modification. Epigenetic processes regulate gene expression through DNA methylation, histone modification, and non-coding RNA (ncRNAs) without altered DNA sequences. Hypermethylation of ABCB1 and demethylation of ABCG2 promoter lead to chemoresistance in ovarian cancer. The loss of RAD51C promoter methylation and the downregulation of BRCA1 methylation have been verified to cause drug resistance. The specific H3K27 methyltransferase EZH2 confers chemoresistance on ovarian cancer cells through H3K27 methylation. A subclass of miRNAs, “epi-miRNAs”, can modulate epigenetic regulators to impact therapeutic responses. miR-152 and miR-185 co-contribute to the cisplatin resistance by directly targeting DNMT1, miR-15a and miR-16 directly target the Bmi-1 (a member of Polycomb complexes). They may serve as potential epigenetic therapeutic targets. Epigenetic therapy including DNMTi and HDACi can increase the number of CD45 + immune cells, active CD8 + T and NK cells in TME, reducing immunosuppression. Thus, the epigenetic therapy combined with immunotherapy may be a promising therapeutic strategy for resistant OC. (HDACs, histone deacetylases; H3K27, histone H3 lysine 27; EZH2, enhancer of zeste homolog 2; DNMTis, DNA methyltransferase inhibitors; HDACis, histone deacetylase inhibitors; Bmi-1: a member of Polycomb complexes)