For many decades the most common anti-cancer treatments have been the use of conventional chemotherapeutic agents. However their broad-based mechanisms (e.g., DNA alkylating agents) usually leads to severe systemic side effects. Today, molecular targeted therapies, which block specific molecules involved in cancer growth or progression, represent an integrative approach to cancer therapy that has already led to breakthrough clinical responses in specific types of cancers. This is particularly evident with several recently developed kinase inhibitors that target EGFR, BCR-ABL, HER2, ALK, VEGFR, mTOR, JAK2, and BRAF.
The discovery of signaling pathways associated with states of “oncogene addiction” has allowed scientifically guided drug discovery strategies to exploit specific tumor cell vulnerabilities, opening up a new paradigm of personalized cancer therapy. However, these are rarely curative, and suffer from the same major limitation associated with traditional chemotherapy drugs—the duration of any observed clinical benefit is invariably short-lived due to the relatively rapid acquisition of drug resistance.
Identifying the specific molecular mechanisms of resistance to chemotherapeutics has been very challenging. As a result, the discovery of second-generation chemotherapeutics that can effectively treat such acquired chemo-drug resistance has been limited. However, the mechanisms of acquired resistance to pathway-targeted drugs—for example, tyrosine kinase inhibitors (TKIs)—have been more tractable to some degree. The discovery has led to the development of follow-on drugs specifically designed to overcome acquired resistance.
As more mechanisms of acquired resistance are unraveled, there are further opportunities to develop new drugs that target the root cause of the resistance process. In conjunction with this, there is a pressing need for more clinically relevant and predictive preclinical models to address the high attrition rate of agents entering clinical trials, and also for the evaluation of new agents in models that replicate acquired resistance mechanisms.
Drug-naïve preclinical models and standard cell-derived xenograft (CDX) models may have genetic and phenotypic characteristics distinct from those patients in the clinic that have relapsed, therefore they would not predict clinical efficacy.
This article outlines the utility of models that are derived from both cell lines and patient-derived xenograft (PDX) models of acquired resistance that can be used to develop specific models of resistance to certain chemotherapeutics and targeted agents.