Mechanisms of Acquired Resistance to Targeted Cancer Therapies

Mark R Lackner; Timothy R Wilson; Jeff Settleman


Future Oncol. 2012;8(8):999-1014. 

In This Article

Abstract and Introduction


Drugs that target genomically defined vulnerabilities in human tumors have now been clinically validated as effective cancer therapies. However, the relatively rapid acquisition of resistance to such treatments that is observed in virtually all cases significantly limits their utility and remains a substantial challenge to the clinical management of advanced cancers. As molecular mechanisms of resistance have begun to be elucidated, new strategies to overcome or prevent the development of resistance have begun to emerge. In some cases, specific mutational mechanisms contribute directly to acquired drug resistance, and in other cases it appears that nonmutational and possibly epigenetic mechanisms play a significant role. This article discusses the various genetic and nongenetic mechanisms of acquired drug resistance that have been reported in the context of 'rationally targeted' drug therapies.


The relatively new paradigm of 'rationally targeted' cancer drug therapies has dramatically impacted the practice of medical oncology, with the discovery and development of 'personalized' cancer medicines that produce remarkable clinical responses in a subset of patients with advanced systemic disease. This has been particularly evident with several of the recently developed kinase inhibitors that target oncogenic forms of EGFR, HER2, BCR–ABL, ALK, JAK2 and BRAF, where clinical activity has been tightly linked to the presence of mutationally activated alleles of the genes encoding the target kinase in a subset of genotype-defined patients. In addition to the clinical successes associated with selective kinase inhibitors, other examples of genotype-associated treatment response have been observed; for example, in the case of treatment of BRCA-mutant breast and ovarian cancers with PARP inhibitors, and in basal cell carcinoma patients defined by mutational activation of the Hh pathway upon treatment with inhibitors of the pathway component SMO. The deep interrogation of a deluge of recently generated cancer genome data, together with ever-accelerating efforts to discover and develop drugs that target a variety of signaling pathways associated with states of 'oncogene addiction', has paved the way for scientifically guided therapeutic strategies to exploit specific tumor cell vulnerabilities.

While there is rapidly growing enthusiasm for this new paradigm of personalized cancer therapy and the opportunity for prospective selection of biomarker-defined patient populations most likely to benefit, there is also the sobering realization that these 'smart' therapies suffer from the same major limitation associated with traditional chemotherapy drugs in the metastatic disease setting; that is, the duration of any observed clinical benefit is invariably short lived, owing to the relatively rapid acquisition of drug resistance.

In the case of the commonly used chemotherapy drugs, establishing specific molecular mechanisms of resistance has been very challenging, and while numerous candidate mechanisms have been described, thus far none of these have led to the discovery of second-generation agents that can effectively manage such acquired drug resistance. In part, this challenge reflects the relatively nonspecific nature of the antitumor mechanisms associated with these drugs, which exert their actions on complex and fundamental processes including nucleotide metabolism, DNA synthesis and repair, and mitosis. On the other hand, mechanisms of acquired resistance to 'pathway-targeted' drugs, such as the various clinically active kinase inhibitors, have been somewhat more straightforward to elucidate and, in a few cases, the discovery of such mechanisms has prompted the development of drugs specifically designed to overcome them.

Mechanisms underlying acquired resistance to pathway-targeted drugs are being pursued largely through two basic strategies. Preclinically, cancer cell line models are being used to recapitulate the clinical experience, providing 'paired' samples of pretreatment drug-sensitive cells and post-treatment cells that manage to escape the consequences of drug exposure, and these largely isogenic cell line pairs can be compared in order to identify molecular mechanisms of acquired drug resistance. In addition, tumor biopsies collected prior to treatment and following post-treatment response and subsequent progression can be similarly compared. In the setting of non-small-cell lung cancer (NSCLC) and melanoma, these two strategies have revealed a seemingly overlapping set of mechanisms derived from each approach, thereby validating the utility of this strategy. For example, secondary mutations in the EGF receptor (EGFR) kinase domain (T790M) in EGFR-mutant NSCLC patients or gain-of-function mutations in NRAS in BRAF-mutant melanoma patients promote drug resistance by reactivating key prosurvival pathways.[1,2] Significantly, such analysis has revealed that acquired drug resistance mechanisms are likely to fall into two fundamentally distinct categories: genetic and nongenetic (or epigenetic). The following sections give an overview of both of these classes of mechanisms of acquired resistance to pathway-targeted anticancer drugs. This is not intended to be a comprehensive review of this important topic, for which there has been a virtual explosion in the number of recently published reports. Rather, the intent is to provide several examples of genetic and nongenetic mechanisms of acquired resistance to the various molecularly targeted oncology drugs that have demonstrated clinical activity – derived from both preclinical cell line modeling studies and from the analysis of clinical specimens – and to discuss how these findings are impacting strategies in which combination drug treatments can be used to overcome, or possibly to prevent, the acquisition of drug resistance.