Abstract P5-02-21: RAB5 is a generic biomarker for ADC efficacy

Abstract

Antibody-drug conjugates (ADCs) have demonstrated impressive activity in recent clinical trials in breast cancer. Such targeted therapeutics strongly depends on the presence of target molecules on the tumor cells, and the presence of such target molecules may determine the response of ADCs. However, ADCs are also dependent on cellular uptake, and factors regulating endocytosis as well as intracellular trafficking may strongly influence ADC activity. We have recently demonstrated that the activity of the HER2 targeted ADC trastuzumab emtansine (T-DM1) is dependent on the expression of RAB5A, a protein regulating endocytosis (1). A significant correlation between Rab5A expression and T-DM1 efficacy was found in a panel of HER2 expressing breast- and ovarian cancer cell lines. This result was verified in the I-SPY2 clinical trial where patients with high RAB5A expression were more likely to achieve a pathological complete response following T-DM1 as a neoadjuvant. The result was further validated in patients treated with T-DM1 in the Kamilla study where patients with a high RAB5A had a longer progression free survival. All ADCs should in principle be dependent on endocytosis to exert their activity. This triggered the investigation of proteins regulating endocytosis as predictive biomarkers for ADCs in general. METHODS: HER2-positive breast and ovarian cancer cell lines were evaluated with respect to the sensitivity and efficacy of treatment with T-DM1, trastuzumab deruxtecan, sacituzumab govitecan and the targeted toxin MH3B1/rGel.. The expression levels of proteins involved in endocytosis and endocytic trafficking including RAB4A, RAB5A and RAB11A were investigated in addition to the molecular drug targets (HER2 and TROP2). Cellular drug sensitivity was correlated to the expression levels of the investigated proteins using both RNA and protein as readout. RESULTS: The early endosome marker RAB5A, was found to correlate positively to the activity of trastuzumab deruxtecan, sacituzumab govitecan and MH3B1/rGel in the HER2 positive cell line panel, confirming the importance of RAB5A expression for the activity of these drugs. A significant correlation was found between RAB5A and drug efficacy using both protein and RNA as a readout. CONCLUSION: The present results indicate RAB5A as a generic predictive biomarker for both ADCs and targeted toxins which both depend on cellular uptake for cytotoxic efficacy. The results supports using both protein and RNA as a readout for RAB5A expression and point towards the development of a RAB5A stratification procedure for ADC and targeted toxin treatment. 1. Engebraaten O, Yau C, Berg K, Borgen E, Garred O, Berstad MEB, Fremstedal ASV, DeMichele A, Veer LV, Esserman L, Weyergang A. RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer. Nature communications 2021;12(1):6427 doi 10.1038/s41467-021-26018-z. Citation Format: Olav Engebraaten, Astrid Medhus, Ane Longva, Anette Weyergang, Kristian Berg. RAB5 is a generic biomarker for ADC efficacy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-21.