Inhibition of brain metastasis by blocking MAPK12 driver kinase functions

在每年160万名被诊断为乳腺癌的女性中，约有10%-16%发生脑转移。 即使有了最先进的临床护理，脑转移瘤患者一年的死亡率也高达20%。 生死存亡。目前，转移性难治性乳腺癌尚无有效的药物治疗。 大脑。因此，迫切需要新颖有效的治疗方法来治疗这一人群。不幸的是， 由于缺乏对脑转移瘤的深入了解，开发脑转移瘤的有效疗法在很大程度上受到了阻碍 脑转移的基本机制，可指导药物开发和临床试验。至 克服挑战，我们进行了史无前例的活体人类亲属组筛选，以揭示 促进小鼠乳腺癌脑转移的新的激酶，因为激酶位于中心结节 癌细胞信号网络对癌症进展/转移至关重要，并可作为治疗药物 目标。在我们确定的与侵袭性脑转移相关的首要候选激酶中，有丝分裂原- 活化蛋白激酶12(MAPK12，又称p38γ)在脑中的作用尚不清楚 但在高度侵袭性的人类乳腺癌和MAPK12高表达的患者中过表达。 表达乳腺癌的人以后脑转移的发生率更高。因此，我们表演了 使用MAPK12过表达的乳腺癌细胞进行实验性脑转移分析，并验证了 MAPK12确实促进了动物的脑转移。MAPK12是MAPK家族的成员，其 过度表达会增加癌细胞的运动性和侵袭性。令人兴奋的是，我们发现MAPK12位于 脑转移丰富的蛋白激酶信号网络的“中枢”，增强脑转移细胞 利用乳酸作为大脑生长的能量来源。此外，MAPK12具有靶向性 临床上用于治疗其他疾病的可用的抑制剂。这里，我们假设激活/ MAPK12的过表达协调乳腺癌细胞中的信号通路促进脑转移， 而MAPK12可通过临床应用的激酶抑制剂被有效地抑制。的主要目标 这一建议是：1)确定MAPK12在自发性脑转移瘤和免疫中的功能作用 称职的脑转移模型，并进一步验证其临床意义；2)研究新的 MAPK12活化机制探讨MAPK12介导乳腺癌脑转移的机制 脑转移癌细胞有效地利用乳酸作为适应和生长的能量来源 3)探索MAPK12作为治疗和/或预防乳腺癌的治疗靶点的潜力 癌症脑转移。这些研究的成功完成将带来对 乳腺癌脑转移和第一代有效的脑转移靶向治疗。 最终，我们的发现将顺利地转化为临床试验，导致新的更好的治疗方法 乳腺癌脑转移患者在绝望中寻找希望。

Among 1.6 million women diagnosed with breast cancer every year, about 10-16% develop brain metastasis. Even with the most advanced clinical care, patients with brain metastasis have a devastating <20% one-year survival. At present, no effective drug treatment exists for patients with refractory breast cancer metastatic to the brain. Therefore, novel and effective therapies are urgently needed for this population. Unfortunately, developing effective therapies for brain metastasis is largely hampered by a lack of in-depth understanding of the basic mechanisms of brain metastasis, which could guide drug development and clinical trials. To surmount the challenge, we have performed an unprecedented in vivo screen of the human kinome to uncover novel kinases that promote breast cancer brain metastasis in mice, because kinases are at the central nodes of cancer cell signaling networks critical for cancer progression/metastasis and are druggable as therapeutic targets. Among the top candidate kinases associated with aggressive brain metastasis we identified, Mitogen- Activated Protein Kinase 12 (MAPK12, also known as p38γ) was not previously known to play roles in brain metastasis but is overexpressed in highly aggressive human breast cancers, and patients with MAPK12 high- expressing breast cancers have higher incidences of brain metastasis later on. Therefore, we performed experimental brain metastasis assays using MAPK12-overexpressing breast cancer cells, and validated that MAPK12 indeed promotes brain metastasis in animals. MAPK12 is a member of the MAPK family and its overexpression increases cancer cell motility and invasion. Excitingly, we identified that MAPK12 is located at the "hub" of a signaling network of brain metastasis-enriched kinases that enhances brain metastatic cells’ utilization of lactate as an energy source for outgrowth in the brain. Furthermore, MAPK12 is targetable with available inhibitors that are used in the clinic for other diseases. Here, we hypothesize that activation/ overexpression of MAPK12 coordinates signaling pathways in breast cancer cells to promote brain metastasis, and MAPK12 may be effectively inhibited by using clinically applicable kinase inhibitors. The major goals of this proposal are 1) Determine the functional roles of MAPK12 in spontaneous brain metastasis and in immune competent brain metastasis models, and further validating their clinical relevance; 2) Investigate novel mechanisms of MAPK12-mediated breast cancer brain metastasis by focusing on how MAPK12-activated brain metastatic cancer cells efficiently use lactate as an energy source for adaptation and outgrowth in the brain; 3) Explore the potential of MAPK12 as a therapeutic target for the treatment and/or prevention of breast cancer brain metastasis. The successful completion of these studies will bring about new understanding of breast cancer brain metastasis and the first generation of effective brain metastasis-targeted therapies. Ultimately, our findings will be smoothly translated to clinical trials, leading to new and better treatments for breast cancer brain metastasis patients in dire search of hope.