Co-administration of MDR1 and BCRP or EGFR/PI3K inhibitors overcomes lenvatinib resistance in hepatocellular carcinoma.
Co-administration of MDR1 and BCRP or EGFR/PI3K inhibitors overcomes lenvatinib resistance in hepatocellular carcinoma.
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MDR1 和 BCRP 或 EGFR/PI3K 抑制剂联合用药克服了肝细胞癌中的乐伐替尼耐药性
DOI：
10.3389/fonc.2022.944537
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发表时间：
2022
影响因子：
4.7
通讯作者：
Dong, Jiahong
中科院分区：
文献类型：
--
作者：
Sun, Dawei;Liu, Juan;Wang, Yunfang;Dong, Jiahong
关键词：
Lenvatinib是肝细胞癌（HCC）的一线治疗药物，HCC是最常见的原发性肝癌类型；然而，一些患者对lenvatinib变得难治。晚期HCC患者lenvatinib耐药（LR）的潜在机制尚不清楚。我们的重点是探讨LR的潜在机制和lenvatinib耐药HCC的新治疗方法。特别地，我们建立了Huh7 LR细胞系，并进行了体外、生物信息学和生化分析。此外，我们使用Huh7-LR细胞来源的异种移植小鼠模型来验证体内结果。LR诱导后，多药耐药蛋白1 （MDR1）和乳腺癌耐药蛋白（BCRP）转运蛋白明显上调，表皮生长因子受体（EGFR）、MEK/ERK和PI3K/AKT通路被激活。在体外实验中，埃拉西达（一种MDR1和BCRP双重抑制剂）与lenvatinib共同给药可抑制LR细胞的增殖并诱导凋亡。这些作用可能是由于通过减少集落形成和下调CD133、EpCAM、SOX-9和c-Myc的表达来抑制癌症干细胞（CSCs）的特性。此外，EGFR抑制剂吉非替尼与lenvatinib联合使用可延缓LR细胞的增殖并诱导其凋亡。这些类似的作用可能是由抑制egfr介导的MEK/ERK和PI3K/AKT通路激活引起的。在体内，lenvatinib与埃拉西达或吉非替尼联合使用可抑制肿瘤生长和血管生成。因此，抑制MDR1和BCRP转运体或靶向EGFR/PI3K途径可能克服HCC中的LR。值得注意的是，lenvatinib具有抑制肿瘤增殖和血管生成的作用，因此应用于LR诱导后的HCC治疗。我们的发现可能有助于开发新的有效的HCC治疗策略。
Lenvatinib is the first-line treatment for hepatocellular carcinoma (HCC), the most common type of primary liver cancer; however, some patients become refractory to lenvatinib. The underlying mechanism of lenvatinib resistance (LR) in patients with advanced HCC remains unclear. We focused on exploring the potential mechanism of LR and novel treatments of lenvatinib-resistant HCC. In particular, we established a Huh7 LR cell line and performed in vitro, bioinformatic, and biochemical assays. Additionally, we used a Huh7-LR cell-derived xenograft mouse model to confirm the results in vivo. Following LR induction, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) transporters were markedly upregulated, and the epidermal growth factor receptor (EGFR), MEK/ERK, and PI3K/AKT pathways were activated. In vitro, the co-administration of elacridar, a dual MDR1 and BCRP inhibitor, with lenvatinib inhibited proliferation and induced apoptosis of LR cells. These effects might be due to inhibiting cancer stem-like cells (CSCs) properties, by decreasing colony formation and downregulating CD133, EpCAM, SOX-9, and c-Myc expression. Moreover, the co-administration of gefitinib, an EGFR inhibitor, with lenvatinib retarded proliferation and induced apoptosis of LR cells. These similar effects might be caused by the inhibition of EGFR-mediated MEK/ERK and PI3K/AKT pathway activation. In vivo, co-administration of lenvatinib with elacridar or gefitinib suppressed tumour growth and angiogenesis. Therefore, inhibiting MDR1 and BCRP transporters or targeting the EGFR/PI3K pathway might overcome LR in HCC. Notably, lenvatinib should be used to treat HCC after LR induction owing to its role in inhibiting tumour proliferation and angiogenesis. Our findings could help develop novel and effective treatment strategies for HCC.
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