Abstract
Cancer drug resistance continues to be a major impediment in medical oncology. Clinically, resistance can arise prior to or as a result of cancer therapy. In this review, we discuss different mechanisms adapted by cancerous cells to resist treatment, including alteration in drug transport and metabolism, mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. Making the problem even more challenging, some of these resistance pathways lead to multidrug resistance, generating an even more difficult clinical problem to overcome. We provide examples of these mechanisms and some insights into how understanding these processes can influence the next generation of cancer therapies.
Highlights
Cancer drug resistance continues to be a major impediment in medical oncology
Despite its complex biological nature, many recent successes have been made in the treatment of cancer, including most strikingly chronic myeloid leukemia (CML) and acute promyelocytic leukemia (APL) which have met with great success as well as many cases of pediatric leukemias, Hodgkin’s lymphomas, and testicular cancers (Siegel et al, 2012)
Various anti-cancer therapies were designed to target disease-specific mechanisms that are absent in normal cells. Such strategies include (i) inhibition of a specific oncoprotein, such as targeting the oncogenic fusion proteins Bcr–Abl and PML–RARA with Gleevec and all trans retinoic acid (ATRA) with arsenic trioxide respectively or (ii) activation of a specific immune response against cancerous cells demonstrated by the use of interferon alpha alone or in combination with other anti-cancer drugs including 5-fluorouracil and cytarabine (Raderer and Scheithauer, 1995; Guilhot et al, 1997; Druker et al, 2001; Kreitman et al, 2001; Tallman et al, 2002; Goldman and Melo, 2003; O’Brien et al, 2003; Sawyers, 2004; Kreitman, 2006; Ferrantini et al, 2007; Chin and Gray, 2008; Sellers, 2011)
Summary
With the exception of a handful of children, all patients eventually relapsed, developing a more vigorous form of cancer that was no longer responsive to the treatment: leukemic cells had invaded the blood–brain barrier and colonized the brain “the only place unreachable by chemotherapy....the children died one after the other-felled by virtue of the adaptation designed to protect them...it was a consequence of the body’s defense system subverting cancer treatment” (Mukherjee, 2010) To date, this story still reflects the same tale of cancer treatment where its resistance and relapse remains a major challenge (Wilson et al, 2009).
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