The 2011 Gordon Wilson Lecture: overcoming resistance to targeted cancer drugs

Abstract

During the past decade, molecularly targeted drugs have had a transformative impact on the treatment of several cancer types. Although the clinical benefits of these drugs are impressive, their effects are generally short-lived due to the acquisition of resistance. Unlike most cytotoxic agents, for which resistance mechanisms have remained obscure despite decades of clinical use, an understanding of the molecular basis of resistance to most targeted agents has emerged quickly. This rapid progress has been possible due to advances in molecular technologies that allow genome-wide profiling of patient samples. One important and consistent theme is that resistance is almost invariably associated with restoration of the signaling pathway inhibited by the targeted agent. Here I review examples from three diseases--chronic myeloid leukemia, prostate cancer, and lung cancer--that illustrate these points and reveal how insights into resistance mechanisms can rapidly accelerate the development of second-generation targeted therapies or combination regimens to improve patient outcome.

Fig. 1

Structure of the BCR-ABL kinase domain and the location of several mutations that confer imatinib resistance in patients. (Modified from Ref. , with permission.)

Fig. 2

Cartoon showing the effects of androgen, bicalutamide, or MDV3100 on androgen receptor localization and DNA binding. (Modified from Ref. , with permission.)

Fig. 3

Reciprocal negative feedback between PI3K and androgen receptor signaling pathways in prostate cancer cells with PTEN mutation. (Reprinted from Ref. , with permission.)