Rivera-Soto Ricardo, Yu Yi, Dittmer Dirk P, Damania Blossom
Curriculum in Genetics and Molecular Biology and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
ArQule, Inc., A Wholly Owned Subsidiary of Merck & Co., Inc., Kenilworth, NJ, United States.
Front Oncol. 2021 Jun 18;11:670275. doi: 10.3389/fonc.2021.670275. eCollection 2021.
Non-Hodgkin lymphoma (NHL) are a diverse group of hematological malignancies comprised of over 60 subtypes. These subtypes range from indolent to aggressive. The PI3K/Akt/mTOR pathway has been shown to contribute to cell survival and proliferation and is constitutively active in most NHL. MK-7075 (miransertib) and MK-4440 are small molecules that effectively inhibit Akt and have entered clinical development. Using and models of NHL, we explored targeting the kinase Akt with miransertib and MK-4440 alone or in combination with the mTORC1 inhibitor, rapamycin (sirolimus). Both Akt inhibitors inhibited the pathway and NHL proliferation in a subtype-dependent manner. However, these compounds had a minimal effect on the viability of primary B-cells. Importantly, the combination of miransertib and sirolimus synergistically reduced cell proliferation in NHL, including in one indolent subtype, e.g., follicular lymphoma (FL), and two aggressive subtypes, e.g., diffuse large B-cell lymphoma (DLBCL) and primary effusion lymphoma (PEL). To establish efficacy, we used several xenograft models of FL, DLBCL, and PEL. The results obtained were consistent with the studies. The FL xenograft was highly sensitive to the inhibition of Akt alone; however, the tumor burden of PEL xenografts was only significantly reduced when both Akt and mTORC1 were targeted. These data suggest that targeting the PI3K/Akt/mTOR pathway with Akt inhibitors such as miransertib in combination with mTOR inhibitors serves as a broadly applicable therapeutic in NHL.
非霍奇金淋巴瘤（NHL）是一组多样的血液系统恶性肿瘤，由60多种亚型组成。这些亚型从惰性到侵袭性不等。PI3K/Akt/mTOR通路已被证明有助于细胞存活和增殖，并且在大多数NHL中呈组成性激活。MK-7075（米瑞替尼）和MK-4440是有效抑制Akt的小分子，已进入临床开发阶段。我们使用NHL的[具体模型名称1]和[具体模型名称2]模型，探索单独使用米瑞替尼和MK-4440或与mTORC1抑制剂雷帕霉素（西罗莫司）联合靶向激酶Akt。两种Akt抑制剂均以亚型依赖的方式抑制该通路和NHL增殖。然而，这些化合物对原代B细胞的活力影响极小。重要的是，米瑞替尼和西罗莫司联合使用可协同降低NHL中的细胞增殖，包括一种惰性亚型，如滤泡性淋巴瘤（FL），以及两种侵袭性亚型，如弥漫性大B细胞淋巴瘤（DLBCL）和原发性渗出性淋巴瘤（PEL）。为了确定疗效，我们使用了几种FL、DLBCL和PEL的异种移植模型。获得的结果与[具体研究]一致。FL异种移植对单独抑制Akt高度敏感；然而，只有当同时靶向Akt和mTORC1时，PEL异种移植的肿瘤负荷才会显著降低。这些数据表明，用米瑞替尼等Akt抑制剂联合mTOR抑制剂靶向PI3K/Akt/mTOR通路可作为NHL中一种广泛适用的治疗方法。
