USE OF HSP90 INHIBITORS TO OVERCOME TRASTUZUMAB RESISITANCE IN THE MINOR VARIANT OF HER2 P95HER2 IN BREAST CANCER

Authors: Alraddadi, Mohammed;
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Abstract

Breast cancer is one of the most commons cancers worldwide. A number of mutations in several genes lead to breast cancer. In particular, HER2 amplification occurs in about 20 percent of breast cancer cases.HER2 is targeted by trastuzumab which is a food and drug administration (FDA) approved drug for HER2 positive breast cancer. However, there are several mechanisms for trastuzumab resistance. One mechanism is a HER2 variant that is lacking the binding domain with the antibody. P95HER2 is a variant of HER2 which lacks the extracellular domain, so trastuzumab has no effect on it. On the other hand, P95HER2 is an HSP90 client protein, therefore; targeting the HSP90 may have a good outcomes in reducing the P95HER2 variant. This study will evaluate a cell line that contains the minor variant P95HER2 which is resistant to trastuzumab, and to test whether two different HSP90 inhibitors are effective in controlling the proliferation of the cells. Aim 1: To characterize in terms of proliferation and phosphorylation of Akt and MAPK model cell lines including BT-474 with full length HER2 and T47D-P95HER2 with P95HER2 variant, in addition to MCF10A cells as a negative control. The P95HER2 will be examined to confirm P95HER2 is an HSP90 client as measured by co-immunoprecipitation. Aim 2: To determine the effect on viability by growth inhibition of BT-474 and T47D-P95HER2 cells to trastuzumab in the presence of EGF and TGF-α in cell cultures. Aim 3: To evaluate whether HSP90 inhibitors can reduce cell proliferation and the activation of MAPK and Akt on the T47D-P95HER2 cells.