Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer

Abstract

The success of tyrosine kinase inhibitors (TKIs) in select patients with non-small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.

Fig 1.

Comparison of the number and distribution of secondary resistance mutations in the tyrosine kinase domains of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). In EGFR-positive patients with acquired tyrosine kinase inhibitor (TKI) resistance, four different second-site mutations in EGFR have been identified in clinical specimens. The gatekeeper mutation T790M (bold) is the most common, present in approximately 50% of patients at the time of resistance. The remaining EGFR secondary mutations are present at low frequencies. In contrast, seven different secondary mutations have been identified in ALK-positive patients at the time of TKI resistance, including the L1196M gatekeeper mutation (bold). Despite this wider distribution of secondary mutations within the ALK tyrosine kinase domain, such mutations are found in only approximately 30% of patients.

Fig 2.

Mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors identified in EGFR-positive patient specimens. Activation of EGFR results in downstream signaling through the PI3K/AKT and RAS/RAF/MEK/ERK pathways, leading to cell proliferation and survival. The highlighted yellow boxes designate points along these pathways and others that have been associated with resistance to EGFR TKIs: (1) EGFR gene amplification, (2) secondary mutations in EGFR (eg, T790M), (3) MET amplification, (4) hepatocyte growth factor (HGF) –mediated MET activation, (5) HER2 amplification, (6) PIK3CA mutations, and (7) BRAF mutations.