(UroToday.com) Muscle-invasive urothelial carcinoma (MIBC) is treated with cisplatin-based chemotherapy even though it is only moderately efficient in many patients due to tumor heterogeneity and development of cisplatin resistance. To provide urothelial carcinoma (UC) patients with more personalized and efficient therapeutic options molecular biomarkers for predicting chemotherapy response are needed. They report a mass spectrometry proteomics analysis of cisplatin resistant UC cell lines (UCC) compared to naïve controls and tissue microarray analysis of identified biomarker candidates.
They performed a comparative LC-MS/MS mass spectrometry analysis of three conventional UCC (RT112, T24, J82) and their cisplatin resistant sublines (LTTs). They identified common more highly abundant proteins among the LTTs constituting candidates for new cisplatin resistance protein biomarkers. The Top 10 proteins (APOBEC3B, COTL1, GLIPR1, LANCL1, NAMPT, NRP1, PDLIM7, TOP2A, TXNDC17, and GSR) were assessed by immunohistochemical stainings on a tissue microarray (TMA) from chemo-naïve samples of 100 MIBC patients who underwent postoperative platinum-based chemotherapy. In addition, the functional involvement of APOBEC3B, NAMPT, NRP1, TOP2A, and GSR in cisplatin resistance was investigated by siRNA knockdown in LTTs.
Increased protein levels of PDLIM7, TOP2A, and GSR were independently associated with worse overall survival in multivariate analysis. Kaplan-Meier analyses demonstrated high protein levels of PDLIM7, TOP2A, NAMPT, and APOBEC3B to be significantly correlated with poor overall survival. siRNA knockdown of NAMPT, GSR, and particularly of TOP2A and APOBEC3B re-sensitized cisplatin resistant LTT sublines to cisplatin treatment.
In summary, they identified and validated new protein biomarker candidates for cisplatin resistance in UC. Their increased protein levels contribute to poor survival of bladder cancer patients, they are functionally involved in cisplatin resistance and some are even targetable.
Presented by: Henning Reis, MD, PhD, University of Duisburg-Essen, Essen, Germany
Written by: Stephen B. Williams, MD, MBA, MS @SWilliams_MD on Twitter during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain