Horiuchi Dai, Camarda Roman, Zhou Alicia Y, Yau Christina, Momcilovic Olga, Balakrishnan Sanjeev, Corella Alexandra N, Eyob Henok, Kessenbrock Kai, Lawson Devon A, Marsh Lindsey A, Anderton Brittany N, Rohrberg Julia, Kunder Ratika, Bazarov Alexey V, Yaswen Paul, McManus Michael T, Rugo Hope S, Werb Zena, Goga Andrei
Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
Nat Med. 2016 Nov;22(11):1321-1329. doi: 10.1038/nm.4213. Epub 2016 Oct 24.
Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.
三阴性乳腺癌（TNBC）是预后最差的乳腺癌亚型，其细胞缺乏雌激素受体（ER）、孕激素受体（PR）以及ERBB2（也称为HER2）受体的表达。由于缺乏经过验证的分子靶点，目前尚无针对该亚型癌症的靶向治疗方法。我们之前报道过，涉及MYC（一种调控数百个基因表达的关键的、多效性转录因子）的信号传导在三阴性（TN）肿瘤中比在受体阳性（RP）肿瘤中异常地高。直接抑制MYC的致癌转录活性一直颇具挑战性。在此，通过进行针对激酶组的短发夹RNA（shRNA）筛选，我们在与MYC的合成致死相互作用中鉴定出PIM1（一种非必需的丝氨酸 - 苏氨酸激酶）。PIM1在TN肿瘤中的表达高于RP肿瘤，并且与激素和HER2阴性肿瘤患者的不良预后相关。小分子PIM激酶抑制剂通过抑制MYC的致癌转录活性并恢复内源性细胞周期抑制剂p27的功能，在患者来源的肿瘤异种移植（PDX）和MYC驱动的乳腺癌转基因小鼠模型中，阻止了具有升高的MYC表达的人TN肿瘤的生长。我们的研究结果值得对MYC表达升高的TN肿瘤患者进行PIM激酶抑制剂的临床评估。
