A major barrier to the successful management of cancer is the development of resistance to therapy. Chemotherapy resistance can either be an intrinsic property of malignant cells developed prior to therapy, or acquired following exposure to anti-cancer drugs. Given the impact of drug resistance to the overall poor survival of cancer patients, there is an urgent need to better understand the molecular pathways regulating this malignant phenotype. In this chapter we describe some of the molecular pathways that contribute to drug resistance in cancer, the role of a microenvironment deficient in oxygen (hypoxia) in malignant progression, and how hypoxia can be a significant factor in the development of drug resistance. We conclude by proposing potential therapeutic approaches that take advantage of a hypoxic microenvironment to chemosensitize therapy-resistant tumours.
Keywords: Autophagy; Chemotherapy; Drug resistance; Glyceryl trinitrate; HIF-1; Hypoxia; Metastasis; Nitric oxide; PD-1/PD-L1; Tumor microenvironment.