PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway
PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway
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DOI：
10.1038/s41419-024-06502-2
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发表时间：
2024-04-12
影响因子：
9
通讯作者：
Zheng，Junfang
中科院分区：
文献类型：
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作者：
Ma，Yuanzhen;Fang，Zhiyu;Zheng，Junfang
表皮生长因子受体（EGFR）靶向药物（厄洛替尼等）用于治疗多种类型的肿瘤。EGFR在大多数三阴性乳腺癌（TNBC）患者中高度表达。然而，在临床试验中，只有一小部分TNBC患者受益于EGFR靶向药物，耐药机制尚不清楚。在此，我们发现PDZ domain containing 1（PDZK 1）在厄洛替尼耐药的TNBC细胞中下调，表明PDZK 1下调与TNBC中的厄洛替尼耐药相关。PDZK 1与EGFR结合。通过这种相互作用，PDZK 1通过增强EGFR与c-Cbl的结合来促进EGFR降解，并通过阻碍EGFR二聚化来抑制EGFR磷酸化。我们还发现PDZK 1在TNBC组织中特异性下调，并与TNBC患者的不良预后相关。体外和体内功能测定表明，PDZK 1抑制TNBC的发展。EGFR表达的恢复或激酶抑制剂治疗分别逆转了PDZK 1过表达或敲低诱导的细胞恶性程度。PDZK 1过表达在体外和体内均使TNBC细胞对厄洛替尼敏感。总之，PDZK 1是TNBC的重要预后因素，也是逆转TNBC细胞中厄洛替尼耐药性的潜在分子治疗靶点。
Epidermal growth factor receptor (EGFR)-targeted drugs (erlotinib, etc.) are used to treat multiple types of tumours. EGFR is highly expressed in most triple-negative breast cancer (TNBC) patients. However, only a small proportion of TNBC patients benefit from EGFR-targeted drugs in clinical trials, and the resistance mechanism is unclear. Here, we found that PDZ domain containing 1 (PDZK1) is downregulated in erlotinib-resistant TNBC cells, suggesting that PDZK1 downregulation is related to erlotinib resistance in TNBC. PDZK1 binds to EGFR. Through this interaction, PDZK1 promotes EGFR degradation by enhancing the binding of EGFR to c-Cbl and inhibits EGFR phosphorylation by hindering EGFR dimerisation. We also found that PDZK1 is specifically downregulated in TNBC tissues and correlated with a poor prognosis in TNBC patients. In vitro and in vivo functional assays showed that PDZK1 suppressed TNBC development. Restoration of EGFR expression or kinase inhibitor treatment reversed the degree of cell malignancy induced by PDZK1 overexpression or knockdown, respectively. PDZK1 overexpression sensitised TNBC cells to erlotinib both in vitro and in vivo. In conclusion, PDZK1 is a significant prognostic factor for TNBC and a potential molecular therapeutic target for reversing erlotinib resistance in TNBC cells.