Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma

Abstract

The advent of genomics has led to the identification of specific "driver" mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance.

Fig. 1

Mechanisms of resistance to targeted therapies. a. Example of a drug-sensitive tumor. Downstream signaling is decreased upon addition of a targeted inhibitor. b–e. Examples of mechanisms promoting drug-resistant tumors. b. On-target mutations block the ability of the drug to bind to and inhibit the target oncoprotein, allowing continued signaling to promote tumor survival. c. Upregulation of a distinct receptor tyrosine kinase sustains signaling through a critical signaling pathway despite continued inhibition of the primary oncoprotein with the targeted drug. d. Mutational activation of a protein involved in a critical downstream signaling pathway reactivates the pathway below the level of inhibitor blockade. e. Activation of pro-survival signaling networks can prevent inhibitor-mediated apoptosis