Overcoming Therapy Resistance in HER2‐positive Breast Cancer with the Dual Rac/Cdc42 Inhibitor MBQ‐167

Abstract

Breast cancer is one of the leading causes of cancer-related mortality among women. Of the major types of breast cancer, ~20% are categorized as HER2-positive, which is characterized by overexpression of the human epidermal growth factor receptor (HER2). HER2 activation leads to signaling cascades that result in cell proliferation, survival and metastasis. Clinically, trastuzumab (Herceptin) has been the standard of care for decades. Unfortunately, some patients have intrinsic resistance while others develop resistance within a year of treatment. One of the resistance mechanisms reported in the literature is the compensation of signaling through other receptors that converge on the activation of guanine nucleotide exchange factors (GEFs), which in turn activate the GTPase Rac and its close homolog Cdc42. Rac/Cdc42 are critical factors involved in cell survival and metastasis that have been implicated with therapy resistance, and overexpression of Rac decreases survival in HER2 positive breast cancer patients. Therefore, we developed and characterized the dual Rac/Cdc42 inhibitor MBQ-167 to block the interaction of Rac and Cdc42 with their respective GEFs. Our objective is to test the utility of MBQ-167 to overcome therapy resistance in HER2-positive cells. To accomplish this, we will test the hypothesis that targeting Rac/Cdc42 (downstream effectors of the HER2 receptor) will disrupt signaling and decrease cell viability and metastasis of HER2 positive resistant cells. We performed cell viability assays at different time points and with different concentrations of MBQ-167, trastuzumab and combination of MBQ-167 and trastuzumab. The results herein show that MBQ-167 decreases cell viability of Trastuzumab resistant HER2-positive cells. This data demonstrates the potential of MBQ-167 to overcome HER2 targeted therapy resistance. Our long term objective is to utilize liposomal formulations containing MBQ-167, functionalized with trastuzumab, in order to specifically target our drug towards HER2-positive breast cancer cells.