Growth inhibition of KRAS- and EGFR-mutant lung adenocarcinoma by cosuppression of STAT3 and the SRC/ARHGAP35 axis

Ken Onodera, Akira Sakurada, Hirotsugu Notsuda, Tatsuaki Watanabe, Yasushi Matsuda, Masafumi Noda, Chiaki Endo, Yoshinori Okada

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

The need for effective treatment of KRAS-mutant lung cancer is an emerging issue. Rho GTPase-activating protein 35 (ARHGAP35) is reported to be a possible molecular target for lung adenocarcinoma. We investigated the effect of long-term ARHGAP35 suppression on the proliferation, migration and molecular dynamics of lung adenocarcinomas harboring KRAS and EGFR gene mutations. Lung adenocarcinoma cell lines A549 (KRAS-mutant) and PC9 and H1975 (EGFR-mutants) were used, and ARHGAP35 knockdown was carried out using puromycin. Cell viability, migration and molecular dynamics were assayed 1 month after introducing small hairpin RNA. The compensatory upregulated mechanism was screened by western blotting and confirmed by a specific inhibitor. Finally, we tested the effects of cosuppression of the SRC/ARHGAP35 axis and the identified pathway in vitro. ARHGAP35 suppression was attenuated by long-term knockdown of the target genes. Compensatory mechanisms by SRC and STAT3 caused attenuation in A549 cells. After long-term ARHGAP35 knockdown, both A549 and PC9 cells were more sensitive to treatment with a STAT3 inhibitor. The suppressive effect of ARHGAP35 knockdown on migration was sustained, but only modest, in all cell lines. Synergistic and strong growth inhibition was observed with concomitant use of an SRC inhibitor and a STAT3 inhibitor in A549 cells. STAT3 activation compensated for ARHGAP35 knockdown in lung adenocarcinoma with the KRAS mutation. Moreover, cosuppression of the STAT3 pathway and SRC/ARHGAP35 axis may be an effective strategy for treating lung adenocarcinoma, especially in the presence of a KRAS mutation.

Original languageEnglish
Pages (from-to)1761-1768
Number of pages8
JournalOncology reports
Volume40
Issue number3
DOIs
Publication statusPublished - 09-2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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