New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer

Abstract

The management of non-small cell lung carcinoma (NSCLC) has been transformed by the observation that lung adenocarcinomas harboring mutations in epidermal growth factor receptor (EGFR) are uniquely sensitive to EGFR tyrosine kinase inhibitors (TKI). In these patients, acquired resistance to EGFR-TKI develops after a median of 10 to 14 months, at which time the current standard practice is to switch to conventional cytotoxic chemotherapy. Several possible mechanisms for acquired resistance have been identified, the most common being the development of an EGFR T790M gatekeeper mutation in more than 50% of cases. In this review, we discuss recent advances in the understanding of acquired TKI resistance in EGFR-mutant lung cancer and review therapeutic progress with second generation TKIs and combinations of targeted therapies.

Figure 1

Frequency of acquired resistance mechanisms for EGFR-TKIs. Proportions are based on aggregate data from the two largest rebiopsy series to date, Arcila et al (n=99) and Sequist et al (n=37)(20, 21). MET amplification shown represents cases without co-existing EGFR T790M; another 3-4% of MET amplified cases also harbor the EGFR T790M. Small cell transformation group includes a case with non-small cell neuroendocrine differentiation. Not shown are other rare second site mutations in EGFR, one acquired PIK3CA mutation, and rare acquired beta-catenin mutations (both overlapping with EGFR T790M). Epithelial mesenchymal transition was studied in a small subset, so the prevalence is uncertain. Overall, there remain about one quarter to one third of cases for which the mechanism of acquired resistance is presently unknown.

Figure 2

(A) Differential growth kinetics of isogenic EGFR-mutant TKI-sensitive (exon 19 deletion; blue) and -resistant (exon 19 deletion & T790M; red) cells. Data were derived from total cell counts of PC9 parental (sensitive) and PC9 resistant cells over 72 hours (27). (B) Schematic representing different treatment scenarios for EGFR-mutant lung cancer. Following initial treatment with an EGFR-TKI (e.g. gefitinib or erlotinib), EGFR-mutant tumors may shrink dramatically (blue cells; left). In most cases, progression is due to acquisition of the T790M mutation (red cells; middle). Upon cessation of TKI therapy, faster growing TKI-sensitive cells may repopulate (at times causing a “flare”), allowing the tumor to “re-respond” to a second round of TKI therapy following a drug holiday (right). If resistant tumors are indeed a heterogeneous mix of TKI-sensitive and -resistant cells (middle), continuation of TKI therapy along with chemotherapy following progression (bottom) will target both cell populations more effectively than chemotherapy alone (top). TKI: tyrosine kinase inhibitor