The Second Clinical Medical School of Guangzhou University of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
BMC Cancer. 2023 Aug 8;23(1):732. doi: 10.1186/s12885-023-11243-0.
Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation often obtain de novo resistance or develop secondary resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), which restricts the clinical benefit for the patients. The activation of phosphatidylinositol 3-kinase (PI3K)/AKT signal pathway is one of the most important mechanisms for the EGFR-TKIs resistance beyond T790M mutation. There are currently no drugs simultaneously targeting EGFR and PI3K signal pathways, and combination of these two pathway inhibitors may be a possible strategy to reverse theses resistances. To test whether this combinational strategy works, we investigated the therapeutic effects and mechanisms of combining BYL719, a PI3Kα inhibitor, with gefitinib, an EGFR-TKI inhibitor in EGFR-TKIs resistance NSCLC models induced by PI3K/AKT activation. Our results demonstrated that PIK3CA mutated cells showed increased growth rate and less sensitive or even resistant to gefitinib, associated with increased PI3K/AKT expression. The combination of BYL719 and gefitinib resulted in synergistic effect compared with the single agents alone in EGFR-mutated NSCLC cells with PI3K/AKT activation. The inhibition of AKT phosphorylation by BYL719 increased the antitumor efficacy of gefitinib in these cell lines. Moreover, the combined effect and mechanism of gefitinib and BYL719 were also confirmed in the NSCLC cells and patient-derived organoids under 3D culture condition, as well as in vivo. Taken together, the data indicate that PIK3CA mutation induces more aggressive growth and gefitinib resistance in NSCLC cells, and the combination treatment with gefitinib and BYL719 is a promising therapeutic approach to overcoming EGFR-TKIs resistance induced by PI3K/AKT activation.
非小细胞肺癌（NSCLC）患者的表皮生长因子受体（EGFR）突变常导致对 EGFR 酪氨酸激酶抑制剂（EGFR-TKIs）的获得性耐药或继发性耐药，这限制了患者的临床获益。磷脂酰肌醇 3-激酶（PI3K）/AKT 信号通路的激活是 EGFR-TKIs 耐药的最重要机制之一，超出了 T790M 突变。目前尚无同时针对 EGFR 和 PI3K 信号通路的药物，联合使用这两种通路抑制剂可能是逆转这些耐药性的一种可行策略。为了验证这种联合策略是否有效，我们研究了 PI3Kα 抑制剂 BYL719 与 EGFR-TKI 抑制剂吉非替尼联合治疗由 PI3K/AKT 激活诱导的 EGFR-TKIs 耐药 NSCLC 模型的治疗效果和机制。我们的结果表明，PIK3CA 突变细胞表现出更高的生长速度，对吉非替尼的敏感性降低甚至耐药，与 PI3K/AKT 表达增加有关。与单药治疗相比，在具有 PI3K/AKT 激活的 EGFR 突变 NSCLC 细胞中，BYL719 与吉非替尼联合使用具有协同作用。BYL719 抑制 AKT 磷酸化增加了这些细胞系中吉非替尼的抗肿瘤疗效。此外，在 3D 培养条件下的 NSCLC 细胞和患者来源的类器官以及体内，也证实了吉非替尼和 BYL719 的联合作用和机制。综上所述，数据表明 PIK3CA 突变诱导 NSCLC 细胞更具侵袭性生长和吉非替尼耐药，吉非替尼和 BYL719 的联合治疗是克服 PI3K/AKT 激活诱导的 EGFR-TKIs 耐药的一种有前途的治疗方法。
