Cisplatin resistance in germ cell tumours: models and mechanisms

Abstract

SUMMARYRecent years have led to a better understanding of the mechanisms underlying cisplatin response and resistance in germ cell tumours (GCT), and several promising targets have been identified. Two main mechanisms of the responsiveness to DNA damaging agents have been postulated. Firstly, GCT readily activate a DNA damage response, but show deficits in several damage repair pathways. In particular, they have been found to have defects in interstrand crosslink repair and in homologous recombination (HR). Secondly, GCT, especially embryonal carcinoma (EC) cells, show a hypersensitive apoptotic response to DNA damage, which activates p53, and leads to up-regulation of the pro-apoptotic factors Noxa, Puma and Fas in non-resistant EC. These cells fail to activate p21 which induces a G1/S arrest, but accumulate in G2/M phase. In the absence of functional p53, family members like p73 and GTAp63 might be important in initiating this response. Mechanisms involved in cisplatin resistance are as follows: down-regulation of Oct4 (e.g. as a result of hypoxia, treatment with retinoic acid or exposure to cisplatin) and failure to induce Puma and Noxa; changes in the expression levels of micro-RNAs such as miR-17/-106b, miR-302a, or miR-371 to -373; elevated levels of MDM2 and cytoplasmic translocation of p21 by phosphorylation; and activation of the PDGFRb/PI3K/pAKT pathway. Several approaches to overcome resistance have been successfully examined in vitro and in vivo, including PARP inhibitors, especially in cells showing deficient HRrepair; stabilization of p53 using nutlin-3; inhibition of several components of the PI3K/pAKT pathway using small molecules; and DNA demethylation by 5-azacytidine or 5-aza-deoxy-cytidine, among others. Many of these substances deserve further exploration, alone or in combination with DNA damaging agents, and the most promising approaches should be taken forward to clinical testing. Targeted therapy based on mechanistic insights holds the promise to turn cisplatin-resistant GCT into a curable disease.

A Rare Case of Embryonal Carcinoma in a Patient with Turner Syndrome without Y Chromosomal Material but Mutations in <b><i>KIT</i></b>, <b><i>AKT1</i></b>, and <b><i>ZNF358</i></b> Demonstrated Using Exome Sequencing

“…This is related to 5-year survival rates of 5-10% in the usage of a 2-drug treatment strategy, with the combination of gemcitabine and paclitaxel as a well-established choice [Koychev et al, 2011]. Research is ongoing in order to better understand the phenomenon of resistance, as well as assessing new targets and thus new treatments to overcome it, and thereby improving chances of cure in patients harboring resistance [Jacobsen and Honecker, 2015]. Recommendations on surgical debulking are currently suggested to be carried out at high volume centers [Rice et al, 2014].…”

Investigational targeted therapies for the treatment of testicular germ cell tumors

“…The PI3K-AKT signaling pathway has been suggested to be involved in tumor growth and cisplatin resistance of GCTs [40,86]. PI3K-AKT signaling can be activated by KIT, EGFR, PDGFR, and/or EGFR/ERBB2 activation [40].…”

Will Testicular Germ Cell Tumors Remain Untargetable?

“…This vulnerability is due to the decreased threshold to undergo apoptosis in response to DNA damage, the reduced ability to repair cisplatin-induced DNA fragmentation and the lack of active pumps to export cisplatin outside the cell [54][55][56]. The decreased ability to repair damaged DNA is due to the common presence of defects in inter-strand crosslink repair and in homologous recombination [57]. Additionally, the vast majority of TGCTs maintain high intratumoral levels of the wild-type p53 protein that upregulates pro-apoptotic factors such as Noxa, Puma and Fas [57].…”

“…The decreased ability to repair damaged DNA is due to the common presence of defects in inter-strand crosslink repair and in homologous recombination [57]. Additionally, the vast majority of TGCTs maintain high intratumoral levels of the wild-type p53 protein that upregulates pro-apoptotic factors such as Noxa, Puma and Fas [57]. They also present high expression of BCL2-associated X protein, and low levels of the anti-apoptotic protein BCL2 [58].…”

“…Many genetic and epigenetic alterations that affect the five known signaling pathways in the pathogenesis of TGCTs have been found to be associated with cisplatin-resistance [56]. However, none of the above-mentioned genes have allowed discrimination between chemo-resistant and chemo-sensitive cell lines and no apoptotic regulators have been demonstrated to be determinants for chemo-resistance in Bin vitro^studies [57]. The pro-apoptotic protein p53 commonly mutated in other solid tumors is rarely mutated in TGCT, including resistant TCGT [84].…”