Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) 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 [KDD]) 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. Additionally, YAP1 involvement was investigated in pathological specimens. YAP1 was activated by short-term EGFR-TKI treatment in EGFR mutation-positive lung cancer cells. In addition, inhibiting YAP1 function using small interfering RNA 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.

中文翻译：

---

EGFR酪氨酸激酶抑制剂与TEAD抑制剂联合治疗可增强EGFR突变阳性肺癌的抑瘤效果

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）是EGFR突变阳性肺癌的一线疗法。EGFR-TKIs具有良好的治疗效果。然而，很大一部分EGFR突变阳性肺癌患者随后会复发。一些癌细胞在 EGFR-TKI 的初始治疗后存活下来，这种最初的存活可能与随后的复发有关。因此，我们的目标是克服 EGFR-TKIs 的初始生存率。我们假设 yes 相关蛋白 1 (YAP1) 参与 EGFR-TKI 的初始生存，并且我们证实了 EGFR-TKI 和 YAP1-TEAD 通路抑制剂的联合作用。使用从 EGFR 突变阳性肺癌患者建立的 KTOR27（EGFR 激酶结构域重复 [KDD]）肺癌细胞系和市售的 PC-9 和 HCC827（EGFR 外显子 19 缺失）肺癌细胞系。这些细胞用于评估 TEAD 抑制剂 VT104 的体外和体内效果。此外，在病理标本中研究了 YAP1 的参与情况。在 EGFR 突变阳性肺癌细胞中，短期 EGFR-TKI 治疗可激活 YAP1。此外，使用小干扰RNA抑制YAP1功能可增加对EGFR-TKI的敏感性。VT104 和 EGFR-TKI 联合治疗在体外和体内表现出比单独使用 EGFR-TKI 更好的肿瘤抑制效果。此外，无论 EGFR-TKI 暴露前 YAP1 的定位状态如何，都观察到 VT104 和 EGFR-TKI 的联合效应。这些结果表明，TEAD抑制剂和EGFR-TKI联合治疗可以改善EGFR突变阳性肺癌患者的预后。