A tale of two approaches: complementary mechanisms of cytotoxic and targeted therapy resistance may inform next-generation cancer treatments

Abstract

Chemotherapy and molecularly targeted approaches represent two very different modes of cancer treatment and each is associated with unique benefits and limitations. Both types of therapy share the overarching limitation of the emergence of drug resistance, which prevents these drugs from eliciting lasting clinical benefit. This review will provide an overview of the various mechanisms of resistance to each of these classes of drugs and examples of drug combinations that have been tested clinically. This analysis supports the contention that understanding modes of resistance to both chemotherapy and molecularly targeted therapies may be very useful in selecting those drugs of each class that will have complementing mechanisms of sensitivity and thereby represent reasonable combination therapies.

Fig. 1.

Summary of main points.

Fig. 2.

Cellular mechanisms of resistance to cytotoxic chemotherapies and molecular targeted therapies. Resistance to cytotoxic therapy is commonly a result of failure of the drug to reach its intended target. This is mediated by enhanced activity of drug transporters, induction of emergency response genes to increase the repair of damaged DNA or dampening of mitochondrial-dependent apoptotic cell death. The main mechanisms for resistance to targeted therapies are genetic alteration/mutation of the target itself, persistent activation of downstream signaling pathways, bypass mechanisms such as activation of alternative driver-oncogenes or other downstream signaling pathways or pathway-independent mechanisms such as epigenetic alterations. Yellow boxes represent the major mechanisms of resistance to cytotoxic therapies, and green boxes denote resistance mechanisms to target therapies. Letters and numbers in each box correspond with those in Tables I, II, and III detailing resistance mechanisms.

Fig. 3.

Examples of rational combinations of chemotherapies and targeted therapies. Chemo- and targeted therapies are interrelated in that the limitations of one approach can be overcome by corresponding benefits of the other. Several combinations of chemotherapy and targeted therapy for different types of cancers are depicted by corresponding color boxes. (A) Combinations of HER-2 targeted therapies and chemotherapies for breast cancers demonstrate synergistic effects as well as inhibition of multiple RTKs. (B) Rapalog and methotrexate combinations for renal cancers and leukemias improve their effects through MDR reversal. (C) Erlotinib induces G₁-arrest and inhibition of efflux pumps, which can synergize with chemotherapeutics, and sequential administration of EGFR TKIs following chemotherapy provides a greater effect than concurrent administration. Also, resistance to chemo- and targeted therapies converges on an inability to undergo apoptosis, and pharmacological inhibition of pro-apoptotic members including the Bcl-2 family could overcome chemotherapy drug resistance. (D) Addition of bevacizumab can promote the efficacy of combined cytotoxic agents through the improved delivery of cytotoxic agents via normalization of the tumor vasculature. On the contrary, it could reconstitute the blood–brain barrier in GBM, preventing the diffusion of anticancer drugs.