Novel Pathways in the Control of Lineage Plasticity in Neuroendocrine Prostate Cancer

摘要 对癌症靶向治疗的获得性抵抗是一种日益增长的未得到满足的临床需求。前列腺癌(PCA)中， 下一代雄激素受体(AR)途径抑制剂的成功一直受到发展的阻碍 抗药性。在许多情况下，这种获得性阻力涉及AR轴通过 几种不同的机制。然而，很明显，另一种抵抗机制是 在前列腺癌细胞重新编程的驱动下经历谱系可塑性，采用AR非依赖性 状态，并获得神经内分泌表型，使他们生长和生存，并逃避AR治疗。 更有效和更持久的AR靶向导致神经内分泌前列腺癌发病率增加 (NEPC)，这是一种极具侵袭性、高增殖性和转移性的PCa变体。因此， 了解控制NEPC分化的分子机制是一个迫切的未得到满足的临床需求。 我们的初步数据已经证实，蛋白激酶C L/I是一种新的肿瘤抑制因子。我们的 最近发表的数据表明，在人类NEPC患者中，PKC 1/I的表达下调，并且其 Lost促进新陈代谢重新编程，从而维持增加的增殖和表观遗传变化 PCa细胞需要经历癌细胞向NEPC分化的可塑性。PKCl/I结果的损失 在导致S增产的丝氨酸和一碳途径代谢上调中- 腺苷蛋氨酸(SAM)，它是DNA和组蛋白甲基化的甲基供体。我们新的未出版的 数据表明，PKCl/I除了对产生SAM至关重要外，还直接调节DNMT1和 EZH2是利用SAM的关键甲基转移酶，是染色质的终极修饰物。因此，我们的 最重要的假设是，PKCl/I不仅通过调节SAM的产生，而且还通过调节表观遗传修饰物 在NEPC分化期间对PCA基因组的破坏造成了新的漏洞，可以在治疗上加以利用。 这项提议将解决三个关键问题：(目标1)PKCl/I介导的磷酸化是如何 在NEPC分化过程中控制EZH2和DNMT1的功能？(目标2)DNMT1和EZH2如何- PKCl/I下游依赖的表观遗传重编程有助于不同NEPC的获得 特征是什么？(目标3)PHGDH(丝氨酸生物合成的限制酶)单独或与之联合抑制 表观遗传抑制物是治疗NEPC肿瘤的有效方法？圆满完成 这一建议将使我们进一步了解支配血统的分子机制。 在NEPC分化过程中的可塑性，并有助于识别可能导致新的 在这个致命的前列腺癌中的疗法。

SUMMARY Acquired resistance to targeted therapies in cancer is a rising unmet clinical need. In prostate cancer (PCa), the success of next-generation androgen receptor (AR) pathway inhibitors have been hampered by the development of drug resistance. This acquired resistance involves, in many cases, the reactivation of the AR axis through several different mechanisms. However, it has become apparent that an alternative mechanism of resistance is driven by the reprogramming of prostate cancer cells to undergo lineage plasticity to adopt an AR-independent state and to acquire a neuroendocrine phenotype, that allow them to grow and survive and escape AR-therapy. More potent and sustained AR targeting has driven an increased incidence of neuroendocrine prostate cancer (NEPC), which is an extremely aggressive, highly proliferative and metastatic PCa variant. Therefore, understanding the molecular mechanisms that govern NEPC differentiation is a pressing unmet clinical need. Our preliminary data have identified protein kinase C (PKC)l/i as a novel tumor suppressor in NEPC. Our recently published data demonstrate that the kinase PKCl/i is downregulated in human NEPC patients, and its loss promotes a metabolic reprogramming that sustains increased proliferation, as well as epigenetic changes needed by PCa cells to undergo cancer cell plasticity towards NEPC differentiation. The loss of PKCl/i results in the upregulation of the serine and one-carbon pathway metabolism that leads to increased production of S- adenosine methionine (SAM), which is the methyl donor for DNA and histone methylation. Our new unpublished data demonstrate that PKCl/i, in addition to be critical to produce SAM, also directly regulates DNMT1 and EZH2, key methyltransferases that utilize SAM, and are the ultimate chromatin modifiers. Therefore, our overarching hypothesis is that PKCl/i by regulating not only SAM generation but also the epigenetic modifiers of the PCa genome during NEPC differentiation creates new vulnerabilities that can be exploited therapeutically. Three key questions will be addressed in this proposal: (Aim 1) How does PKCl/i-mediated phosphorylation control EZH2 and DNMT1 functions during NEPC differentiation? (Aim 2) How does DNMT1 and EZH2- dependent epigenetic reprogramming downstream of PKCl/i contribute to the acquisition of the different NEPC traits? (Aim 3) Is PHGDH (the limiting enzyme in serine biosynthesis) inhibition alone or in combination with epigenetic inhibitors an effective therapeutic approach for treating NEPC tumors? The successful completion of this proposal will allow us to advance our understanding of the molecular mechanisms governing lineage plasticity during NEPC differentiation and help in the identification of new vulnerabilities that could lead to novel therapies in this lethal PCa.