Overcoming drug resistance in cancer

Drug resistance is developed when cancer cells become tolerant to treatments such as systemic chemotherapy, targeted therapy, or/and immunotherapy. Resistance to anticancer drugs is a multifactorial phenomenon that occurs through multiple mechanisms. Subpopulations of cancer cells with various genetic composition co-existing in primary tumors have different sensitivity to chemotherapy or targeted drugs, such that initial treatment can eliminate only a fraction of cancer cells and those that are less sensitive to the treatment could survive. Following exposure to targeted anticancer drugs, resistance may emerge due to alterations of drug targets, which may be either a secondary mutation in the target protein or epigenetic changes that alter protein expression levels in the cancer cells, alterations in the tumor microenvironment, and other cellular and molecular mechanisms. Many of the mechanisms of targeted drug resistance coalesce into a few convergences, including oncogenic signaling pathway reactivation (downstream re-engagement of original signaling effectors), bypass (recruitment of a parallel pathway converging on the same downstream signaling output), and indifference (development of a cellular state independent of the initial therapeutic target). 1 Konieczkowski D.J. Johannessen C.M. Garraway L.A. A Convergence-Based Framework for Cancer Drug Resistance. Cancer Cell. 2018; 33: 801-815https://doi.org/10.1016/j.ccell.2018.03.025 Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Resistance to current monotherapy or combination therapies remains a challenge to cancer treatment, as it is responsible for most relapses, which are major causes of cancer patient death.