Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors

Abstract

Owing to its exquisite chemotherapy sensitivity, most patients with metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy. However, up to 30% of patients with advanced GCT exhibit cisplatin resistance, which requires intensive salvage treatment, and have a 50% risk of cancer-related death. To identify a genetic basis for cisplatin resistance, we performed whole-exome and targeted sequencing of cisplatin-sensitive and cisplatin-resistant GCTs. MethodsMen with GCT who received a cisplatin-containing chemotherapy regimen and had available tumor tissue were eligible to participate in this study. Whole-exome sequencing or targeted exoncapture-based sequencing was performed on 180 tumors. Patients were categorized as cisplatin sensitive or cisplatin resistant by using a combination of postchemotherapy parameters, including serum tumor marker levels, radiology, and pathology at surgical resection of residual disease. ResultsTP53 alterations were present exclusively in cisplatin-resistant tumors and were particularly prevalent among primary mediastinal nonseminomas (72%). TP53 pathway alterations including MDM2 amplifications were more common among patients with adverse clinical features, categorized as poor risk according to the International Germ Cell Cancer Collaborative Group (IGCCCG) model. Despite this association, TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model. Actionable alterations, including novel RAC1 mutations, were detected in 55% of cisplatin-resistant GCTs. ConclusionIn GCT, TP53 and MDM2 alterations were associated with cisplatin resistance and inferior outcomes, independent of the IGCCCG model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this tumor subtype. A substantial portion of cisplatin-resistant GCTs harbor actionable alterations, which might respond to targeted therapies. Genomic profiling of patients with advanced GCT could improve current risk stratification and identify novel therapeutic approaches for patients with cisplatin-resistant disease.

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

“…These findings could also be extended to other cancers since the Rac1 P29S hotspot mutation has been identified in head and neck, and endometrial cancers (22). A 5% incidence in Rac1 mutations (Rac1 G12V , Rac1 G12R , Rac1 P34R , Rac1 Q61R , and Rac1 Q61K ) has been found in germ cell testicular tumors, which makes these tumors, along with melanoma, the cancer types with the highest incidence of Rac1 mutations reported to date (23). Gain-of-function mutants Rac1 A159V (paralogous to A146 mutants in KRas) and Rac1 Q61R (paralogous to Q61 mutants in KRas) have been also identified in head and neck, and prostate cancer, respectively (22).…”

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

“…Cisplatin resistance in GCTs is of multifactorial origin and involves mechanisms such as (i) an impaired apoptosis induction due to an altered p53/MDM2/MYCN axis, (ii) deficient DNA mismatch repair, (iii) overactivation of the PI3K/AKT/mTOR signalling pathway, (iv) tissue differentiation, and (v) overexpression of multidrug-resistance proteins, among others (Honecker et al, 2009;Feldman et al, 2014;Juliachs et al, 2014;Jacobsen & Honecker, 2015;Oing et al, 2015;Bagrodia et al, 2016). Studying resistance mechanisms has led to several single-arm phase I/ II studies evaluating single-targeted agents, that is, the mTOR inhibitor everolimus (Mego et al, 2016;Fenner et al, 2018) or the tyrosine kinase inhibitors sunitinib (Feldman et al, 2010;Oechsle et al, 2011a,b), pazopanib (Necchi et al, 2017), or tivantinib (Feldman et al, 2013).…”

Recent developments in the management of germ cell tumors

“…Alterations in KIT and KRAS genes are the most frequent non-synonymous mutations found in GCTs, suggesting that these oncogenes may play an important role in the pathogenesis and growth of these tumors [42, 43, 46]. Nevertheless, a clinical trial of the KIT inhibitor imatinib did not demonstrate antitumor activity against platinum-refractory GCTs positive for KIT expression by immunohistochemistry [47].…”

“…It is possible that targeted inhibition of the KIT pathway may be necessary but not sufficient on its own to achieve lethality in these tumors. Furthermore, in contrast to imatinib-sensitive malignancies such as gastrointestinal stromal tumors, KIT mutations in GCTs are mainly localized on exon 17 and are thus more likely to confer resistance to imatinib [43]. …”

“…Bagrodia et al [43] showed that 25 of 104 (24%) cisplatin-resistant tumors had genetic defects within the TP53/MDM2 pathway compared with 2 of 76 (2.6%) of the cisplatin sensitive tumors (P<0.001). Of note, patients in the cisplatin-resistant cohort had a low death rate (23.1%) and it is unclear whether these patients who succumbed to their disease following salvage platinum-based treatments (such as TIP and high-dose carboplatin) were the ones who had TP53/MDM2 defects or these alterations only predict resistance to first-line cisplatin-based chemotherapy.…”