Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Cancer Sci. 2023 Jan;114(1):164-173. doi: 10.1111/cas.15579. Epub 2022 Sep 21.
Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) with a broad coverage against ALK mutations, has demonstrated dramatic effects in patients with ALK-rearranged lung cancer. The mechanisms of acquired resistance to lorlatinib by secondary ALK compound mutations have recently been reported; however, resistance mechanisms other than secondary mutations remain unclear. Here, we investigated the molecular mechanisms of the acquired resistance in ALK-rearranged lung cancer cells in vitro. We established two different lorlatinib-resistant ALK-rearranged lung cancer cell lines (H3122LR and A925LLR) via long-term administration of lorlatinib. These resistant cells did not harbor the secondary ALK mutations and showed cross-resistance to the other kinds of ALK-TKIs (crizotinib or alectinib) compared with the parental cells; however, these resistant cells overexpressed the phosphorylated human epidermal growth factor receptor 3 (HER3) protein and the ligand of HER3 (neuregulin 1; NRG1). Pharmacological inhibition of HER3 with pan-HER inhibitors or genetic knockdown of HER3 with siRNA resensitized H3122LR and A925LLR cells to lorlatinib in vitro, indicating that H3122LR and A925LLR acquired resistance by NRG1/HER3 activation. These findings demonstrated that targeting NRG1/HER3 is a potential novel therapeutic option for lorlatinib-resistant ALK-rearranged lung cancer.
洛拉替尼是一种第三代间变性淋巴瘤激酶（ALK）-酪氨酸激酶抑制剂（TKI），对 ALK 突变具有广泛的覆盖范围，在 ALK 重排的肺癌患者中显示出显著疗效。最近已经报道了次级 ALK 复合突变导致对洛拉替尼获得性耐药的机制；然而，除了次级突变之外的耐药机制仍不清楚。在这里，我们研究了体外 ALK 重排肺癌细胞获得性耐药的分子机制。我们通过长期给予洛拉替尼建立了两种不同的洛拉替尼耐药的 ALK 重排肺癌细胞系（H3122LR 和 A925LLR）。与亲本细胞相比，这些耐药细胞不携带次级 ALK 突变，并且对其他类型的 ALK-TKI（克唑替尼或阿来替尼）表现出交叉耐药；然而，这些耐药细胞过度表达磷酸化人表皮生长因子受体 3（HER3）蛋白和 HER3 的配体（神经调节蛋白 1；NRG1）。用 pan-HER 抑制剂抑制 HER3 或用 siRNA 基因敲低 HER3 可使 H3122LR 和 A925LLR 细胞在体外对洛拉替尼重新敏感，表明 H3122LR 和 A925LLR 通过 NRG1/HER3 激活获得耐药性。这些发现表明，针对 NRG1/HER3 是洛拉替尼耐药的 ALK 重排肺癌的一种潜在新的治疗选择。
