Co-targeting Pathways May Improve Efficacy of EGFR-TKIs in Lung Cancer

Treatment with a single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) can no longer be considered adequate for patients with EGFR-mutant non-small cell lung cancer (NSCLC), according to a study presented at the American Association for Cancer Research (AACR) Annual Meeting 2016.¹

Intrinsic or acquired resistance often limits the clinical effectiveness of EGFR TKIs for patients with NSCLC with EGFR mutations. One mechanism of resistance is via the activation of signal transducer and activator of transcription 3 (STAT3). Further, EGFR blockade enriches lung cancer stem cells through NOTCH3-dependent signaling while the oncogene Src triggers activation of YAP and NOTCH signaling.

Therefore, researchers sought to demonstrate that single EGFR TKI treatment cannot overcome STAT3 and Src in EGFR-mutant NSCLC cell lines and to examine whether the combination of gefitinib with compounds that targets STAT3 and Src suppresses the mechanisms of resistance.

Researchers found that 9 days after gefitinib treatment, STAT3 mRNA level was significantly increased, and they observed a dramatic increase in the fraction of ALDH+ cells upon treatment with gefitinib. TPCA-1, a compound that targets STAT3, increased sensitivity to gefitinib in PC-9 cells; however, neither inhibited Scr or YAP.

Adding saracatinib, a compound that targets Scr, to gefitinib and TPCA-1 was highly synergistic and abrogated STAT3, Scr, and YAP.

Results also showed that high expression of STAT3 and YAP were significantly associated with shorter median progression-free survival among 64 patients with EGFR-mutant NSCLC treated with first-line EGFR TKIs. Median progression-free survival was 9.6 months (95% CI, 5.9 – 14.1) for patients with low STAT3 compared with 18.4 months (95% CI, 8.8 – 30.2) for patients with high STAT3 mRNA expression (P < .001). Median progression-free survival was 9.6 months (95% CI, 7.7 – 15.2) for those with low YAP and 23.4 months (95% CI, 13.0 – 28.1) for patients with high YAP mRNA expression (P = .005).

Median progression-free survival was 25.7 months (95% CI, 8.5 – 60.9) for patients with low STAT3 and YAP mRNA vs 9.4 months (95% CI, 2.8 – 15.2) for those with high STAT3 and YAP mRNA, and 14.1 (95% CI, 8.2 – 23.4) months for other combinations (P = .004).

The findings ultimately suggested that a clinical trial evaluating the co-targeted inhibition of STAT3 and Src is warranted.

Reference

1. Karachaliou N, Chaib I, Pilotto S, et al. Cotargeting EGFR, STAT3 and Src-Notch pathways: a promising approach to improve the efficacy of EGFR-TKIs in the treatment of NSCLC patients. Poster presentation at: AACR Annual Meeting 2016; April 16-20, 2016; New Orleans, LA.