Lehmann Brian D, Bauer Joshua A, Schafer Johanna M, Pendleton Christopher S, Tang Luojia, Johnson Kimberly C, Chen Xi, Balko Justin M, Gómez Henry, Arteaga Carlos L, Mills Gordon B, Sanders Melinda E, Pietenpol Jennifer A
Breast Cancer Res. 2014 Aug 8;16(4):406. doi: 10.1186/s13058-014-0406-x.
Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC.
We determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR + TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability.
PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects.
While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR + TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.
三阴性乳腺癌（TNBC）是一组生物学特性各异的异质性癌症，这导致了不同的临床结局。此前，我们鉴定出一种具有管腔表型且表达雄激素受体（AR+）的TNBC亚型。源自这些管腔AR+肿瘤的TNBC细胞具有高频的磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA）突变。本研究的目的是确定单独靶向磷酸肌醇3-激酶（PI3K）或与AR拮抗剂联合使用是否对AR+ TNBC有效。
我们确定了AR+和AR- TNBC临床病例中激活PIK3CA突变的频率。使用AR+ TNBC细胞系和异种移植模型，我们评估了单独使用或与AR拮抗剂联合使用的PI3K抑制剂对肿瘤细胞生长和活力的有效性。
PIK3CA激酶突变具有高度克隆性，在AR+ TNBC中比在AR- TNBC中更常见（40%对4%），并且常与PI3KCA基因座的同时扩增相关。在AR+ TNBC细胞中，当PI3K/mTOR抑制剂与基因或药理学上的AR靶向联合使用时，具有相加的生长抑制作用。我们还在异种移植肿瘤研究中分析了比卡鲁胺+/-泛PI3K抑制剂GDC-0941或双PI3K/mTOR抑制剂GDC-0980的联合使用情况，并观察到了相加效应。
虽然约三分之一的TNBC患者对新辅助/辅助化疗有反应，但最近的研究表明，AR+ TNBC患者从当前的标准护理化疗方案中获益的可能性要小得多，需要研究新的靶向治疗方法。在本研究中，我们表明激活的PIK3CA突变在AR+ TNBC中富集；并且，我们表明在用PI3K抑制剂与AR拮抗剂联合治疗后，AR+ TNBC细胞系模型的生长和活力显著降低。这些结果为预先选择具有生物标志物（AR表达）的TNBC患者以研究AR拮抗剂与PI3K/mTOR抑制剂联合使用提供了理论依据。
