Resisting Resistance: Targeted Therapies in Lung Cancer

Abstract

Drug resistance inevitably limits the efficacy of all targeted therapies including tyrosine kinase inhibitors (TKIs). Understanding the biological underpinnings of TKI resistance is key to the successful development of future therapeutic strategies. Traditionally, mechanisms of TKI resistance have been viewed under a dichotomous lens. Tumor cells are TKI-sensitive or TKI-refractory, exhibit intrinsic or acquired resistance, and accumulate alterations within or outside the target to promote their survival. Such classifications facilitate our comprehension of an otherwise complex biology, but are likely an oversimplification. Recent studies underscore the multifaceted, genetically heterogeneous nature of TKI resistance, which evolves dynamically with changes in therapy. In this Review, we provide a broad framework for understanding the diverse mechanisms of resistance at play in oncogene-driven lung cancers.

Keywords: NSCLC; Resistance; tyrosine kinase inhibitor (TKI).

Figure 1. Oncogenic Drivers in Lung Adenocarcinoma

(A) The distribution of known oncogenic driver alterations in lung adenocarcinoma is shown, with estimated percentages for each driver. For an estimated 40% of lung adenocarcinomas, the underlying genetic alteration(s) remain unknown. Approximately 25% of lung adenocarcinomas carry an activating KRAS mutation, for which targeted therapies are not yet available. (B) There are many tyrosine kinase inhibitors (TKIs) currently in use in the clinic or undergoing active development, which target the validated oncogenic drivers in NSCLC. Examples are listed. Asterisks indicate TKIs which have been approved by the Food and Drug Administration for use in patients with NSCLC harboring the indicated genetic alterations.

Figure 2. An Evolutionary Model of Drug Resistance in Cancer Cells

This figure depicts different models of the evolution of acquired resistance to targeted therapies in cancer cells. In the ‘pre-existing clones model,’ a few tumor cells harbor a pre-existing resistance mechanism prior to the exposure to a tyrosine kinase inhibitor (TKI). These tumor cells with pre-established resistance mechanisms can survive and rapidly proliferate under the selective pressure of a TKI, becoming the predominant cell population. The tumor population as a whole will continue to be heterogeneous. Alternatively, in the ‘persister evolution model,’ a small subpopulation of cells (represented in light blue) may adopt a relatively quiescent, reversible drug-tolerant persister state induced by the initial insult of the TKI exposure. This allows the survival of the persister cells and their subsequent propagation. The persister cells present a window of opportunity for the acquisition of resistance mechanisms, leading to the establishment of fully drug-resistant cells. In the ‘mixed model,’ there are pre-existing drug-resistant clones as well as drug-tolerant persister cells in the TKI-naïve cell population, which evolve under the selective pressure of the TKI until fully drug-resistant tumor clones are established. The ratio of various drug-resistant clones will differ in each tumor and will dynamically change over time in concert with changes in therapy.