PTEN Is Involved in Sunitinib and Sorafenib Resistance in Renal Cell Carcinoma

Abstract

Background/Aim: Targeted receptor tyrosine kinase inhibitor (TKI) is a standard treatment in advanced renal cell carcinoma (RCC). However, the role of PTEN in TKI resistance remains poorly understood. We aimed to determine the functional role of PTEN knockout and analyse the predictive significance of PTEN expression for TKI treatment in RCC. Materials and Methods: We developed PTEN knockout cells in RCC cell lines using the CRISPR-Cas9 system and analysed the effect of PTEN knockout on spheroid formation and resistance to sunitinib and sorafenib. Results: PTEN knockout promoted spheroid formation and decreased sunitinib/sorafenib sensitivity in RCC cell lines. PTEN immunohistochemistry in 74 metastatic RCCs treated with sunitinib and sorafenib revealed negative PTEN expression in 23% of samples. Kaplan-Meier analysis showed a significant association of negative PTEN expression with poor progression-free survival in metastatic RCC treated with sunitinib and sorafenib (p=0.024) or sunitinib alone (p=0.009). Conclusion: PTEN may be a biomarker and therapeutic target in patients with metastatic RCC.Renal cell carcinoma (RCC) accounts for around 90% of all renal tumours, and its incidence has been steadily increasing by 2-4% each year (1). More than 30% of patients diagnosed with RCC have metastatic disease (2). Patients with metastatic RCC have an approximately 13 months' median survival and a 5-year survival rate under 10% (3). Sunitinib is an oral multi-target tyrosine kinase inhibitor (TKI), which has potent anti-angiogenic effects and direct anti-tumour activities due to the inhibition of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and stem cell growth factor receptor (4). Sunitinib treatment is used as a first-line therapy for metastatic RCC (5, 6) and significantly prolongs overall survival in metastatic RCC (7). Although approximately 70% of the patients show an initial response to sunitinib, eventually, sunitinib resistance and disease progression occur. Recent evidence has shown that the mechanisms of sunitinib resistance may be multifactorial (8-10); however, the mechanisms that underpin sunitinib resistance are not fully elucidated. Therefore, there is an urgent need to clarify the mechanisms of sunitinib resistance.Phosphatase and Tensin Homolog Deleted from Chromosome 10 (PTEN) is a tumour-suppressive protein (11).The PTEN gene has both recurrent point mutations and focal deletions in RCC (12,13). PTEN has been reported to antagonize the phosphoinositol-3-kinase (PI3K)/PTEN/AKT signalling pathway, which plays a crucial role in cell growth, differentiation, survival and drug resistance in RCC (14,15). The Cancer Genome Atlas data showed that bi-allelic loss of PTEN is rare and associated with poor overall survival in RCC (16,17). Although some studies have reported the prognostic significance of PTEN for TKI treatment (18,19), the role of PTEN in sunitinib and sorafenib resistance in RCC has not been fully elucidated.In this study, we aimed to analyse the effect ...

Identification of MX2 as a Novel Prognostic Biomarker for Sunitinib Resistance in Clear Cell Renal Cell Carcinoma

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