Uncovering the mechanistic basis of MAGEA5/A10 driven resistance to chemotherapeutic drugs

Abstract

Melanoma Antigen Genes (MAGEs) are defined as cancer‐testis antigens due to their unique expression pattern. There are two families of MAGEs, Type I and Type II. Type I MAGEs are expressed in the testis and in no other normal somatic tissue and then re‐expressed in many cancers. Type II MAGEs on the other hand, are ubiquitous in their expression.. The MAGE‐A family are members of the type 1 family located on the X chromosome. Type I MAGEs, considered to be true cancer‐testis antigens are all located on the X chromosome. Previous studies show that reversible DNA methylation of CpG sites upstream of MAGE‐A promoters regulates their expression. Many members of the MAGE1 subfamily cause increase in proliferative phenotypes. However, MAGEA5 and MAGEA10 expressing cells, demonstrated resistance to high doses of chemotherapeutic agent 5‐flurouracil. We aim to understand the mechanism behind this resistance. We will perform RNA‐Sequencing on cells expressing MAGEA5/A10 and control cells and determine protein binding partners of MAGEA5/A10 using IP‐Mass Spectrometry. In addition, we will test the hypothesis that in the heterogenous tumor cell population, MAGEA5/A10 is expressed in the cancer “stem cells” and that is responsible for driving chemo‐resistance. We will also test resistance of these cells to other chemotherapeutic agents such as taxols.