Abstract
Therapeutic resistance remains a major cause of cancer-related deaths. Resistance can occur from the outset of treatment or as an acquired phenomenon after an initial clinical response. Therapeutic resistance is an almost universal phenomenon in the treatment of metastatic cancers. The advent of molecularly targeted treatments brought greater efficacy in patients whose tumors express a particular target or molecular signature. However, resistance remains a predictable challenge. This article provides an overview of somatic genomic events that confer resistance to cancer therapies. Some examples, including BCR–Abl, EML4–ALK, and the androgen receptor, contain mutations in the target itself, which hamper binding and inhibitory functions of therapeutic agents. There are also examples of somatic genetic changes in other genes or pathways that result in resistance by circumventing the inhibitor, as in resistance to trastuzumab and BRAF inhibitors. Yet other examples results in activation of cytoprotective genes. The fact that all of these mechanisms of resistance are due to somatic changes in the tumor’s genome makes targeting them selectively a feasible goal. To identify and validate these changes, it is important to obtain biopsies of clinically resistant tumors. A rational consequence of this evolving knowledge is the growing appreciation that combinations of inhibitors will be needed to anticipate and overcome therapeutic resistance.
Highlights
The fundamental challenge in all anti-cancer therapeutics is resistance
A second example of a druggable gene fusion somatic event, and the first in solid tumors, is the EML4–ALK gene fusion found in 5% of non-small cell lung cancers (NSCLC)
To the imatinib story, two recent reports have discovered secondary mutations in the kinase domain of the ALK gene that appear to be responsible for resistance to crizotinib and to two other unrelated ALK inhibitors (Choi et al, 2010; Sasaki et al, 2011)
Summary
The fundamental challenge in all anti-cancer therapeutics is resistance. This is true of all forms of therapy, in early disease and in advanced metastatic cancers. Emerging biological observations in prostate cancer have indicated that most CRPC cells are still dependent on the AR signaling for proliferation and survival, and in CRPC cells, the AR is activated by multiple mechanisms that cannot be effectively suppressed by castration and currently clinically used antiandrogens (Agoulnik and Weigel, 2006).
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