Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation-positive Lung Cancer.

Autor:	Ogimoto T; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Ozasa H; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Tsuji T; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.; Department of Anatomy and Molecular Cell Biology, Graduate School of Medicine, Nagoya University, Nagoya, Japan., Funazo T; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Yamazoe M; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Hashimoto K; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Yoshida H; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Hosoya K; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Ajimizu H; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Nomizo T; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Yoshida H; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Hamaji M; Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Menju T; Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Yoshizawa A; Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan., Date H; Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Hirai T; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Apr 02; Vol. 23 (4), pp. 564-576.
DOI:	10.1158/1535-7163.MCT-23-0371
Abstrakt:	EGFR-tyrosine kinase inhibitors (TKI) are the first-line therapies for EGFR mutation-positive lung cancer. EGFR-TKIs have favorable therapeutic effects. However, a large proportion of patients with EGFR mutation-positive lung cancer subsequently relapse. Some cancer cells survive the initial treatment with EGFR-TKIs, and this initial survival may be associated with subsequent recurrence. Therefore, we aimed to overcome the initial survival against EGFR-TKIs. We hypothesized that yes-associated protein 1 (YAP1) is involved in the initial survival against EGFR-TKIs, and we confirmed the combined effect of EGFR-TKIs and a YAP1-TEAD pathway inhibitor. The KTOR27 (EGFR kinase domain duplication) lung cancer cell lines established from a patient with EGFR mutation-positive lung cancer and commercially available PC-9 and HCC827 (EGFR exon 19 deletions) lung cancer cell lines were used. These cells were used to evaluate the in vitro and in vivo effects of VT104, a TEAD inhibitor. In addition, YAP1 involvement was investigated in pathologic specimens. YAP1 was activated by short-term EGFR-TKI treatment in EGFR mutation-positive lung cancer cells. In addition, inhibiting YAP1 function using siRNA increased the sensitivity to EGFR-TKIs. Combination therapy with VT104 and EGFR-TKIs showed better tumor-suppressive effects than EGFR-TKIs alone, in vitro and in vivo. Moreover, the combined effect of VT104 and EGFR-TKIs was observed regardless of the localization status of YAP1 before EGFR-TKI exposure. These results suggest that combination therapy with the TEAD inhibitor and EGFR-TKIs may improve the prognosis of patients with EGFR mutation-positive lung cancer. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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