Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer.
Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer.
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DOI：
10.1038/nm.4507
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发表时间：
2018-05
期刊：
影响因子：
82.9
通讯作者：
Westbrook TF
中科院分区：
文献类型：
--
作者：
Nair A;Chung HC;Sun T;Tyagi S;Dobrolecki LE;Dominguez-Vidana R;Kurley SJ;Orellana M;Renwick A;Henke DM;Katsonis P;Schmitt E;Chan DW;Li H;Mao S;Petrovic I;Creighton CJ;Gutierrez C;Dubrulle J;Stossi F;Tyner JW;Lichtarge O;Lin CY;Zhang B;Scott KL;Hilsenbeck SG;Sun J;Yu X;Osborne CK;Schiff R;Christensen JG;Shields DJ;Rimawi MF;Ellis MJ;Shaw CA;Lewis MT;Westbrook TF
三阴性乳腺癌（TNBC）是一种侵袭性的乳腺癌亚型，每年有超过20万名女性被诊断出来，并且难以接受靶向治疗。尽管TNBC含有多种过度活跃的受体酪氨酸激酶（RTK），但到目前为止，RTK抑制剂在TNBC患者中基本上无效。我们开发了一种广泛有效的TNBC治疗策略，该策略基于联合抑制共享负调节因子PTPN12的受体。之前，我们和其他人发现酪氨酸磷酸酶PTPN12是TNBC中经常失活的肿瘤抑制因子。PTPN12抑制几种rtk，表明PTPN12缺陷导致多种rtk的异常激活和对这些受体的共同依赖。这反过来又导致了ptpn12缺陷tnbc可能对联合RTK抑制有反应的治疗假设。然而，人类细胞中受PTPN12抑制的rtk库尚未被系统地探索。通过系统地鉴定被PTPN12抑制的RTK底物（MET、PDGFRb、EGFR等），我们合理地设计了一种联合RTK抑制剂疗法，该疗法可在异质性TNBC模型中诱导有效的肿瘤消退。正交试验表明，PTPN12在配体刺激后被募集到这些受体并抑制它们，从而作为一种限制受体信号传导的反馈机制。PTPN12的癌症相关突变或PTPN12蛋白水平的降低削弱了这种反馈机制，导致这些受体的异常活性。恢复PTPN12蛋白水平抑制来自rtk的信号，包括PDGFRb和MET，并损害TNBC的生存。与单一药物相比，靶向PDGFRb和MET受体的联合抑制剂在体外和体内诱导TNBC细胞凋亡。这种治疗策略在化疗难治性患者衍生的TNBC模型中导致肿瘤消退。值得注意的是，反应与PTPN12缺乏相关，这表明受损的受体反馈可能建立了对这些原致癌受体的联合成瘾。综上所述，我们的数据为在TNBC和其他缺乏受体激活突变的恶性肿瘤中联合使用RTK抑制剂提供了理论依据。
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year and is recalcitrant to targeted therapies. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs), RTK inhibitors have been largely ineffective in TNBC patients thus far. We developed a broadly effective therapeutic strategy for TNBC that is based on combined inhibition of receptors that share the negative regulator PTPN12. Previously, we and others identified the tyrosine phosphatase PTPN12 as a tumor suppressor that is frequently inactivated in TNBC. PTPN12 restrains several RTKs, suggesting that PTPN12 deficiency leads to aberrant activation of multiple RTKs and a co-dependency on these receptors. This in turn leads to the therapeutic hypothesis that PTPN12-deficient TNBCs may be responsive to combined RTK inhibition. However, the repertoire of RTKs that are restrained by PTPN12 in human cells has not been systematically explored. By methodically identifying the suite of RTK substrates (MET, PDGFRb, EGFR, and others) inhibited by PTPN12, we rationalized a combination RTK-inhibitor therapy that induced potent tumor regression across heterogeneous models of TNBC. Orthogonal approaches revealed that PTPN12 was recruited to and inhibited these receptors after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminished this feedback mechanism, leading to aberrant activity of these receptors. Restoring PTPN12 protein levels restrained signaling from RTKs, including PDGFRb and MET, and impaired TNBC survival. In contrast with single agents, combined inhibitors targeting the PDGFRb and MET receptors induced the apoptosis in TNBC cells in vitro and in vivo. This therapeutic strategy resulted in tumor regressions in chemo-refractory patient-derived TNBC models. Notably, response correlated with PTPN12 deficiency, suggesting that impaired receptor feedback may establish a combined addiction to these proto-oncogenic receptors. Taken together, our data provide a rationale for combining RTK inhibitors in TNBC and other malignancies that lack receptor-activating mutations.
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