RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1

Abstract

30Cisplatin-based chemotherapy still remains as one of the primary treatment modalities for 31 OSCC. Several OSCC patients experience relapse owing to development of chemoresistance. To 32 identify key resistance triggering molecules, we performed global proteomic profiling of human 33 OSCC lines presenting with sensitive, early and late cisplatin resistance patterns. From the 34 proteomic profiling study, human RRBP1 was identified to be upregulated in both early and late 35 cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient 36 sample indicates that RRBP1 expression is elevated in chemotherapy-non-responder tumors as 37 compared to chemotherapy-naïve tumors. Knocking out RRBP1 resulted in restoring cisplatin 38 mediated cell death in chemoresistant lines and patient derived cells (PDC). Mechanistically, 39 RRBP1 regulates YAP-1 to induce chemoresistance in OSCC. The chemoresistant PDC 40 xenograft data suggests that knock out of RRBP1 induces cisplatin mediated cell death and 41 facilitates a significant reduction of tumor burden. We also found Radezolid, a novel 42 oxazolidinone antibiotic represses the expression of RRBP1 and restores cisplatin-induced cell 43 death in chemoresistant OSCC. This unique combinatorial approach needs further clinical 44 investigation to target advanced OSCC. Here with for the first time, we uncover the novel role of 45 RRBP1 as potential modulator of cisplatin resistance in advanced OSCC.46 48 developing countries. OSCC is an aggressive form of HNSCC and is the most common cancer 49 among Indian males [1]. Approximately 80,000 new OSCC cases are reported annually with a 50 mortality of 46,000 individuals each year in India. The traditional treatment modalities for 51 advanced OSCC comprises of surgical removal of primary tumors followed by concomitant 52 adjuvant chemoradiotherapy [2]. In addition, neoadjuvant chemotherapy is frequently 53 recommended for surgically unresectable OSCC tumors that reduces tumor and provides more 54 surgical options. Despite having these solutions, the 5-year survival rate of advance tongue 55 OSCC is approximately 50%, indicating a possible resistance to currently available therapeutics. 56 Chemoresistance is one of the important factors for treatment failure in OSCC [3]. Cisplatin 57 alone or in combination with 5-fluorouracil and taxane/docetaxel (TPF) are generally used as 58 chemotherapy regimen for OSCC [4]. But due to chemoresistance development, patients 59 experience relapse which leads to continued tumor growth and metastasis. The chemoresistant 60properties could be attributed to enhanced cancer stem cell population, decreased drug 61 accumulation, reduced drug-target interaction, reduced apoptotic response and enhanced 62 autophagic activities [5]. These hallmarks present the endpoint events, when cancer cell had 63 already acquired chemoresistance. Till date, the causative factors responsible for acquiring 64 chemoresistance in cells are yet not explored. Identifying these molecular triggers ...

Identification of therapeutically potential targets and their ligands for the treatment of OSCC

“…We found that during the period of treatment responsiveness, our genes change their expression level from low to high again, which is the same as the prior treatment. Other studies have also determined the involvement of these genes in resistance generation, for example, SERPINE1 is upregulated in cisplatin-resistant oral cancer cell lines (SCC9, SCC4, and H357) ( 68 ) and paclitaxel-resistant breast cancer ( 44 ). In the context of therapeutic potential, SERPINE1 has been identified as a potential therapeutic target, as it acts as a pro-proliferative oncogenic factor ( 69 ).…”

“…In the context of therapeutic potential, SERPINE1 has been identified as a potential therapeutic target, as it acts as a pro-proliferative oncogenic factor ( 69 ). PLAU is found to be upregulated in cisplatin-resistant oral cancer cell lines ( 68 ). Both PLAU and SERPINE1 were found to be highly expressed in breast cancer patients with adjuvant endocrine therapy and related to shorter disease-free survival and OS ( 70 ).…”