Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland.
Department of Surgery, University Hospital Basel, Basel, Switzerland.
J Mammary Gland Biol Neoplasia. 2023 Jun 9;28(1):13. doi: 10.1007/s10911-023-09539-9.
The protein tyrosine phosphatase SHP2 activates oncogenic pathways downstream of most receptor tyrosine kinases (RTK) and has been implicated in various cancer types, including the highly aggressive subtype of triple-negative breast cancer (TNBC). Although allosteric inhibitors of SHP2 have been developed and are currently being evaluated in clinical trials, neither the mechanisms of the resistance to these agents, nor the means to circumvent such resistance have been clearly defined. The PI3K signaling pathway is also hyperactivated in breast cancer and contributes to resistance to anticancer therapies. When PI3K is inhibited, resistance also develops for example via activation of RTKs. We therefore assessed the effect of targeting PI3K and SHP2 alone or in combination in preclinical models of metastatic TNBC. In addition to the beneficial inhibitory effects of SHP2 alone, dual PI3K/SHP2 treatment decreased primary tumor growth synergistically, blocked the formation of lung metastases, and increased survival in preclinical models. Mechanistically, transcriptome and phospho-proteome analyses revealed that resistance to SHP2 inhibition is mediated by PDGFRβ-evoked activation of PI3K signaling. Altogether, our data provide a rationale for co-targeting of SHP2 and PI3K in metastatic TNBC.
蛋白酪氨酸磷酸酶 SHP2 可激活大多数受体酪氨酸激酶 (RTK) 下游的致癌途径，并且与各种癌症类型有关，包括三阴性乳腺癌 (TNBC) 的高度侵袭性亚型。尽管已经开发出 SHP2 的变构抑制剂，并正在临床试验中进行评估，但这些药物的耐药机制以及规避这种耐药性的方法都尚未明确界定。PI3K 信号通路在乳腺癌中也过度激活，并导致对癌症治疗的耐药性。当 PI3K 被抑制时，例如通过 RTK 的激活，也会产生耐药性。因此，我们在转移性 TNBC 的临床前模型中评估了单独靶向 PI3K 和 SHP2 或联合靶向 PI3K 和 SHP2 的效果。除了 SHP2 单独的有益抑制作用外，双重 PI3K/SHP2 治疗协同地抑制了原发肿瘤的生长，阻止了肺转移的形成，并增加了临床前模型中的存活率。从机制上讲，转录组和磷酸化蛋白质组分析表明，对 SHP2 抑制的耐药性是由 PDGFRβ 引发的 PI3K 信号转导激活介导的。总之，我们的数据为在转移性 TNBC 中联合靶向 SHP2 和 PI3K 提供了依据。
