Acquired and intrinsic resistance to colorectal cancer treatment

Abstract

First line therapy for colorectal cancer (CRC) is usually fluoropyrimidine monotherapy and oxaliplatin, or irinotecan-based therapy. Additionally, targeted therapies such as bevacizumab, aflibercept, ramucirumab, regorafenib, cetuximab and panitumumab are indicated in combination with chemotherapy in metastatic CRC. Resistance of CRC to treatment is the principal rationale for treatment failure. Resistance can be intrinsic (primary resistance) or acquired (secondary resistance). Here, we discuss the classical model of resistance, which focuses primarily on mechanisms involving alterations in drug metabolism, increased drug efflux, secondary mutations in drug targets, inactivation of apoptotic pathways, p53 and DNA damage repair. Other resistance mechanisms, including the Warburg effect, cancer stem cells, intra-tumor heterogeneity and pharmacoepigenomic mechanisms will also be discussed. We conclude the chapter with a systems medicine approach to predict response to treatment for the discovery and validation of predictive biomarkers that are urgently needed.