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三阴性乳腺癌是一种侵袭性很强的乳腺癌，但是直到现在仍然没有用于此类乳腺癌的靶向疗法。如果不进行手术治疗，只有大约30%的三阴性乳腺癌患者能够对化疗产生疗效，而其他患者会对化疗药物产生耐药，并且这种乳腺癌经常向身体远处转移，一旦发生转移就无有效方法进行治疗。 2016年4月13日，美国科学促进会（AAAS）官方期刊《科学·转化医学》在线发表了美国范德堡大学、美国休斯敦卫理公会癌症中心、美国基础医学公司、美国耶鲁大学、秘鲁利马肿瘤医院、秘鲁国家肿瘤研究所的最新研究，找到一种很有希望的三阴性乳腺癌靶向治疗方法。 该研究发现可以帮助解释三阴性乳腺癌对多数治疗耐药的基因变化，这表明一种处于临床开发阶段的靶向疗法可能对三阴性乳腺癌治疗有效。 JAK-STAT是对细胞生长和生存非常重要的一条信号通路，同时也会促进许多肿瘤生长，其中包括乳腺癌。之前一直未能发现推动三阴性乳腺癌发生的明确驱动因素，但是一些证据表明JAK2基因可能在其中发挥一定作用。 该研究收集了111例乳腺癌患者的肿瘤标本，经过测序分析发现JAK2基因在化疗耐药三阴性乳腺癌患者肿瘤标本中的扩增率较高，而这些患者癌症复发往往较快，手术后20个月内的死亡率较高。这些发现表明，JAK2可能在三阴性乳腺癌耐药中发挥作用。 该研究还在患者进行治疗的不同时间进行组织活检，结果发现一部分患者的肿瘤组织中JAK2基因扩增逐渐增加。JAK2在这些肿瘤组织中复制增加率与化疗后肿瘤组织内的JAK2类似，这表明JAK2促进了耐药，并帮助维持了癌症的干细胞样特征。 之后，该研究在细胞系上检测了普通JAK抑制剂的效果，但并不能阻断JAK2基因扩增细胞的肿瘤形成能力。该研究又使用了一种JAK2特异性抑制剂，结果发现这种特异性抑制剂能够显著抑制三阴性乳腺癌在小鼠体内的生长。这些结果都表明JAK2抑制剂可能会在三阴性乳腺癌靶向治疗中发挥作用。 Sci Transl Med. 2016 Apr 13;8(334):334ra53. Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence. Balko JM, Schwarz LJ, Luo N, Estrada MV, Giltnane JM, Dávila-González D, Wang K, Sánchez V, Dean PT, Combs SE, Hicks D, Pinto JA, Landis MD, Doimi FD, Yelensky R, Miller VA, Stephens PJ, Rimm DL, Gómez H, Chang JC, Sanders ME, Cook RS, Arteaga CL. Vanderbilt University, Nashville, TN 37232, USA; Houston Methodist Cancer Center, Houston, TX 77030, USA; Foundation Medicine, Cambridge, MA 02142, USA; Yale University, New Haven, CT 06520, USA; Oncosalud, Lima 41, Perú; Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima 34, Perú. Amplifications at 9p24 have been identified in breast cancer and other malignancies, but the genes within this locus causally associated with oncogenicity or tumor progression remain unclear. Targeted next-generation sequencing of postchemotherapy triple-negative breast cancers (TNBCs) identified a group of 9p24-amplified tumors, which contained focal amplification of the Janus kinase 2 (JAK2) gene. These patients had markedly inferior recurrence-free and overall survival compared to patients with TNBC withoutJAK2amplification. Detection ofJAK2/9p24 amplifications was more common in chemotherapy-treated TNBCs than in untreated TNBCs or basal-like cancers, or in other breast cancer subtypes. Similar rates ofJAK2amplification were confirmed in patient-derived TNBC xenografts. In patients for whom longitudinal specimens were available,JAK2amplification was selected for during neoadjuvant chemotherapy and eventual metastatic spread, suggesting a role in tumorigenicity and chemoresistance, phenotypes often attributed to a cancer stem cell-like cell population. In TNBC cell lines withJAK2copy gains or amplification, specific inhibition of JAK2 signaling reduced mammosphere formation and cooperated with chemotherapy in reducing tumor growth in vivo. In these cells, inhibition of JAK1-signal transducer and activator of transcription 3 (STAT3) signaling had little effect or, in some cases, counteracted JAK2-specific inhibition. Collectively, these results suggest that JAK2-specific inhibitors are more efficacious than dual JAK1/2 inhibitors against JAK2-amplified TNBCs. Furthermore,JAK2amplification is a potential biomarker for JAK2 dependence, which, in turn, can be used to select patients for clinical trials with JAK2 inhibitors. PMID: 27075627 DOI: 10.1126/scitranslmed.aad3001
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