Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Institute of Oncology, Barcelona/Spain
Background: EGFR tyrosine kinase inhibitors (TKIs) induce early activation
of several signaling pathways. Interleukin-6 (IL-6) and signal transducer
and activator of transcription 3 (STAT3) hyper-activation occur following
EGFR TKI therapy in EGFR-mutant NSCLC cells. We explored the relevance
of co-targeting EGFR, STAT3 and Src-YES-associated protein 1 (YAP1)
signaling in EGFR-mutant NSCLC. Methods: We combined in vitro and in
vivo approaches to explore whether concomitant activation of STAT3 and
Src-YAP1 can limit the effectiveness of EGFR TKIs in EGFR-mutant NSCLC
cells and xenograft models. In two cohorts of EGFR-mutant NSCLC patients,
we examined messenger RNA (mRNA) gene expression within signaling
pathways, leading to EGFR TKI resistance. Results: Gefitinib suppressed
EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation
(pSTAT3-Tyr705). In EGFR mutant cells, gefitinib plus TPCA-1 (STAT3 inhibitor)
abolished pSTAT3-Tyr705 but not the YAP1 phosphorylation on tyrosine 357
by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and
AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and
was highly synergistic, according to the combination index. In two EGFR
mutant xenograft mouse models, the triple combination of gefitinib, TPCA-1
and AZD0530 markedly and safely suppressed tumor growth. High levels
of STAT3 or YAP1 mRNA expression were associated with worse outcome
to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free
survival (PFS) was 9.6 (95%CI, 5.9-14.1) and 18.4 months (95%CI, 8.8-30.2)
for patients with high and low STAT3 mRNA, respectively (p