Data from: Exogenous restoration of TUSC2 expression induces responsiveness to erlotinib in wildtype epidermal growth factor receptor (EGFR) lung cancer cells through context specific pathways resulting in enhanced therapeutic efficacy

Expression of the tumor suppressor gene TUSC2 is reduced or absent in most
lung cancers and is associated with worse overall survival. In this study,
we restored TUSC2 gene expression in several wild type EGFR non-small cell
lung cancer (NSCLC) cell lines resistant to the epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their
sensitivity to erlotinib in vitro and in vivo. A significant inhibition of
cell growth and colony formation was observed with TUSC2 transient and
stable expression. TUSC2-erlotinib cooperativity in vitro could be
reproduced in vivo in subcutaneous tumor growth and lung metastasis
formation lung cancer xenograft mouse models. Combination treatment with
intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited
tumor growth and metastasis, and increased apoptotic activity.
High-throughput qRT-PCR array analysis enabling multi-parallel expression
profile analysis of eighty six receptor and non-receptor tyrosine kinase
genes revealed a significant decrease of FGFR2 expression level,
suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to
erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient
transfection, and marked increase of PARP, an apoptotic marker, cleavage
level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by
AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but
not all tested cell lines. TUSC2 inhibits mTOR activation and the latter
cell lines were responsive to the mTOR inhibitor rapamycin combined with
erlotinib. These results suggest that TUSC2 restoration in wild type EGFR
NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as
critical regulators of this activity in varying cellular contexts. The
therapeutic activity of TUSC2 could extend the use of erlotinib to lung
cancer patients with wildtype EGFR.