Martorana Federica, Motta Gianmarco, Pavone Giuliana, Motta Lucia, Stella Stefania, Vitale Silvia Rita, Manzella Livia, Vigneri Paolo
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico-S. Marco", Catania, Italy.
Front Pharmacol. 2021 Apr 29;12:662232. doi: 10.3389/fphar.2021.662232. eCollection 2021.
The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.
丝氨酸/苏氨酸激酶AKT是PI3K/AKT/mTOR信号通路的关键组成部分，因为它在细胞生长、增殖、存活和代谢中发挥着关键作用。该信号通路失调在乳腺癌中很常见，包括激素受体阳性（HR+）疾病、HER2扩增型和三阴性肿瘤。因此，靶向AKT对许多乳腺癌亚型来说是一种有吸引力的治疗选择，尤其是那些对传统治疗耐药的亚型。最近已开发出几种AKT抑制剂，两种ATP竞争性化合物，即卡匹西利和依帕西利，已在I期和II期临床试验中单独、与化疗或与激素药物联合进行了广泛测试。此外，卡匹西利和依帕西利的III期试验已在HR+和三阴性乳腺癌中开展。虽然确定对AKT抑制的反应和耐药的预测生物标志物仍是未满足的需求，但新的联合策略正在研究中，旨在提高这些药物的治疗效果。因此，目前正在进行卡匹西利和依帕西利与CDK4/6抑制剂、免疫检查点抑制剂和PARP抑制剂联合的试验。本综述总结了乳腺癌中AKT抑制的现有证据，报告了临床试验的疗效和毒性数据以及可用的转化相关性，然后重点介绍了这些药物在新联合策略中的潜在用途。
