Abstract LB-B22: TNBC kinase prioritization for targeted therapy after chemotherapy resistance

Abstract

Abstract Introduction: Triple negative breast cancer accounts for 10-15% of all breast cancers yet contribute to high recurrence and metastasis that leads to the death of patients. Lack of molecular therapeutic target for TNBC leaves the chemotherapy as only available options while many develop resistance to chemotherapeutics, leaving patients with TNBC at risk of accumulative toxicities and death. Thus, it is critical to identify unique molecular kinases that contribute to chemotherapy resistance. We hypothesize that differential level of kinase expression stratified based on the chemotherapy response, to discover putative targets. Methods and Material: We performed an in silico search of kinases using mRNA microarray data that are expressed with higher proportion in TNBC patient samples based on the chemotherapeutic response, to identify kinases that contribute to the resistance to neoadjuvant chemotherapy using mRNA sequencing data of 132 patients with TNBC. We then prioritize the putative resistance related kinases, based on priority scoring system we have developed, to select the top candidate kinase for further therapeutics development. Result: Eleven kinases were differentially expressed between the pCR and non-pCR patients samples at baseline, and prioritized based on our scoring system. MELK was selected as a top target kinase given the highest score and biological validation, and currently available inhibitor. Pre-clinical studies of MELK has shown efficacy in vitro and in vivo models. Conclusion: First in human trial of oral MELK inhibitor is currently launched to be tested in actual clinical setting in patients with TNBC, that will offer the opportunity for us to validate our prioritization scoring system and pre-clinical validation. Further clinical validation, which is ongoing, will support our in silico screening followed by a prioritization to select kinase inhibitor development in chemotherapy resistant TNBC. Citation Format: Bora Lim, In Ah Park, Ying Wang, Lakshmi Bollu, Powel Brown, Keith Baggerly, Funda Meric-Bernstam, Naoto Ueno. TNBC kinase prioritization for targeted therapy after chemotherapy resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B22.