Common Genetically Altered Pathways as Targets for Therapy in Pancreatic Cancer

胰腺导管腺癌（PDA）预后极差，5年生存率仅为6%。与许多其他癌症不同，目前的策略并不针对PDA的遗传特征。在某种程度上，这是因为PDA被视为一种由KRAS作为致癌驱动因素主导的疾病。因此，递送至PDA的治疗不是基于生物标志物的靶向治疗，并且化疗是治疗的主要手段。为了确定治疗PDA的新方法，我们通过外显子组测序对>100例PDA病例进行了遗传分析。这些数据揭示了多个通路的畸变。特别是，在>75%的病例中观察到染色体稳定性过程或细胞周期控制的改变。 这些途径是相互关联的，尽管存在共同的问题， KRAS信号的失调。 基因改变可能导致肿瘤特异性脆弱性，可用于治疗。这里 我们将使用两种互补的努力来接近PDA中遗传事件的合理靶向。首先我们得 与染色体保真度相关的多个途径的定义的丢失/突变。这些事件分别是 罕见，但当合并成途径/功能组时，代表>30%的PDA专利。本集团与 其他人发现，基因事件的特定子集代表了可以选择性地 针对性地最值得注意的是生殖系BRCA/PALB 2突变是唯一活跃的III期试验的基础， PDA患者然而，是否与染色体不稳定性相关的其他途径可以被 有效目标尚不清楚。这些发现提供了详细分析的动力， 参与基因组稳定性的基因丢失，PDA中的生物输出，以及选择性治疗 敏感性其次，治疗策略可以恢复肿瘤抑制活性， 破坏PDA并限制增殖以控制疾病。对CDK 4/6的细胞周期调控丧失 在>50%的PDA病例中经常发生p16 ink 4a缺失。因此，CDK 4/6抑制将是 预期在PDA治疗中非常有效。然而，对CDK 4/6抑制剂的反应是可变的。 PDA中的细胞周期调控网络特别复杂，这表明其他遗传事件 影响CDK 4/6抑制的功效。这些发现为确定以下因素提供了基础： 对CDK 4/6抑制剂的持久反应，描述成功的联合治疗，并确定 在PDA的疾病相关模型中使用这些药剂。总的来说，这些研究质疑的假设， 靶向控制基因组稳定性和细胞周期的PDA遗传特征的治疗方法 控制将为治疗提供关键的进展。

Pancreatic ductal adenocarcinoma (PDA) has an exceedingly poor prognosis with a 5-year survival of only ~6%. Unlike many other cancers, current strategies do NOT target genetic features of PDA. In part, this is because PDA is viewed as a disease that is dominated by KRAS as the oncogenic driver. As a result, therapies delivered to PDA are not targeted based on biomarkers, and chemotherapy is the mainstay for treatment. To define new means to treat PDA, we performed genetic analysis of >100 PDA cases by exome sequencing. These data revealed aberrations in multiple pathways. In particular, alterations in chromosome stability processes or cell cycle control were observed in >75% of cases. These pathways are inter-related, and would be expected to remain actionable in spite of the common deregulated KRAS signaling in PDA. Genetic alterations can lead to tumor-specific vulnerabilities that can be exploited for treatment. Here we will approach rational targeting of genetic events in PDA using two complementary efforts. First, we have defined loss/mutation of multiple pathways associated with chromosome-fidelity. These events individually are rare, but when coalesced into pathways/functional groups represent >30% of PDA patents. Our group and others have found that a specific subset of genetic events represent vulnerabilities that can be selectively targeted. Most notably germline BRCA/PALB2 mutations are the basis of the only active Phase III trial for patients with PDA. However, whether other pathways associated with chromosomal instability can be effectively targeted is unknown. These findings provide the impetus for a detailed analysis of the confluence of loss of genes involved in genome stability, resultant biological output in PDA, and selective therapeutic sensitivities. Second, therapeutic strategies can re-instate tumor suppressor activities that have been disrupted in PDA and limit proliferation to control disease. Loss of cell cycle regulatory control over CDK4/6 occurs frequently in >50% of PDA cases through loss of p16ink4a. Therefore, CDK4/6 inhibition would be expected to be exceedingly effective in PDA treatment. However, the response to CDK4/6 inhibitors is variable and cell cycle regulatory networks in PDA are particularly complex suggesting that other genetic events impinge on the efficacy of CDK4/6 inhibition. These findings provide the basis for defining the determinants of durable response to CDK4/6 inhibitors, delineating successful combination therapies, and defining the utility of such agents in disease relevant models of PDA. In total, these studies interrogate the hypothesis that therapeutic approaches targeting genetic features of PDA controlling genome stability and cell cycle control will provide critical advances to treatment.