The major mechanisms of resistance include tumor evolution and tumor heterogeneity acquired secondary genetic alterations signaling pathway feedback loops and bypass mechanisms and the tumor microenvironment 45 drug resistance in each case could involve one or more of these major mechanisms depending on the class of drugs and therapeutic treatment strategies being employed 56. The lack of physiologically relevant drug resistant cancer model systems remains a significant challenge drug resistance in cancer comes in two forms intrinsic resistance and acquired resistance intrinsic resistance is present before a therapy. Using advanced preclinical models to address resistance researchers have traditionally used cancer cell lines to study mutations and other mechanisms that make cancer cells sensitive or resistant to therapies but cell lines do not always share key features of cancers found in patients. Two known models the cancer stem cell csc model and the environment mediated drug resistance emdr model which are not mutually exclusive could explain the origin of resistant cells in the csc model rare populations of cancer stem cells possess tumor initiating properties teicher 2006 nguyen et al 2012