Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2high , GPRC5Ahigh cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition.

中文翻译：

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自适应RSK-EphA2-GPRC5A信号开关触发卵巢癌的化疗耐药性。

转移性癌症通常会激活适应性化疗耐药性，这归因于微环境依赖性表型可塑性和癌细胞的遗传特征。然而，化学治疗本身对非遗传耐药机制的贡献长期以来被忽略。使用高级浆液性卵巢癌（HGSC）患者材料和细胞系，我们在这里描述了一个出乎意料的健壮顺铂和卡铂化疗诱导的ERK1 / 2-RSK1 / 2-EphA2-GPRC5A信号转导，与癌细胞内在和获得性化学耐药有关。从机理上讲，药理学上的抑制或抑制RSK1 / 2可以阻止致癌的EphA2-S897磷酸化和EphA2-GPRC5A的共同调节，从而促进信号转导至肿瘤抑制性酪氨酸磷酸化，进而导致EphA2的下调。与铂类药物联合使用时，RSK抑制剂甚至可以使对铂类耐药性最高的EphA2high细胞，GPRC5Ahigh细胞对治疗诱导的细胞凋亡敏感。在HGSC患者肿瘤中，该孤儿受体GPRC5A仅在癌细胞中表达，并与化疗耐药性和不良的生存率有关。我们的研究结果揭示了铂独特激活的激酶信号传导途径，以引起适应性抗性。他们进一步将GPRC5A鉴定为HGSC预后不良和化学耐药细胞对RSK1 / 2-EphA2-pS897途径抑制的假定脆弱性的标志物。该孤儿受体GPRC5A仅在癌细胞中表达，并与化疗耐药性和较差的存活率有关。我们的研究结果揭示了铂独特激活的激酶信号传导途径，以引起适应性抗性。他们进一步将GPRC5A鉴定为HGSC预后不良和化学耐药细胞对RSK1 / 2-EphA2-pS897途径抑制的假定脆弱性的标志物。该孤儿受体GPRC5A仅在癌细胞中表达，并与化疗耐药性和较差的存活率有关。我们的研究结果揭示了铂独特激活的激酶信号传导途径，以引起适应性抗性。他们进一步将GPRC5A鉴定为HGSC预后不良和化学耐药细胞对RSK1 / 2-EphA2-pS897途径抑制的假定脆弱性的标志物。