Therapeutic targeting of Kras-driven Lung Adenocarcinoma

 描述（由申请人提供）：肺癌是美国癌症死亡的主要原因，表现出约16%的令人沮丧的五年生存率，强调了对新治疗方法的需求。最近开发的靶向治疗药物可有效治疗EGFR、MET和EML 4-ALK中携带特定驱动突变的肺癌亚型，在治疗这些特定肺癌亚型方面取得了重要进展。尽管取得了这些关键进展，但突变型KRAS驱动的肺腺癌（KRAS LADC）（最常见的肺癌形式）的治疗选择仍然有限。我们已经将蛋白激酶C i（PKC i）鉴定为KRAS LADC和肺鳞状细胞癌（LSCC）（两种主要形式的非小细胞肺癌（NSCLC））中的癌基因。PKC 1在这两种NSCLC肿瘤类型中起维持肿瘤起始细胞（TIC）表型的作用。然而，令人惊讶的是，我们发表的和初步的研究表明，PKC 1通过不同的信号传导途径驱动KRAS LADC和LSCC中的TIC表型。初步数据表明：1）PKC 1通过激活多能干因子N 0 TCH 3的表达来驱动KRAS LADC TIC表型; 2）PKC 1通过将ELF 3转录因子募集至N 0 TCH 3启动子来激活N 0 TCH 3表达; 3）PKC 1在Ser 68处磷酸化ELF 3以调节ELF 3占据和N 0 TCH 3启动子的激活; 4）新鉴定的高效和选择性PKC 1抑制剂在体外抑制LADC TIC细胞行为。基于这些数据，我们假设：1）PKC 1调节N 0 TCH 3和参与维持LADC TIC表型的其他基因靶标上的ELF 3启动子占据; 2）新的PKC 1-ELF 3-N 0 TCH 3信号传导轴驱动Kras LADC小鼠模型中Kras介导的LADC起始和进展; 3）我们的新的、有效的和高选择性的PKC 1抑制剂将在KRAS LADC中表现出抗肿瘤活性，和PKC 1-ELF 3-NOTCH 3信号传导中间体将是有用的反应的预测性和药效学生物标志物。这些假设将在三个相互关联的具体目标中进行测试，以：1）评估PKC 1介导的ELF 3磷酸化在NOTCH 3启动子占据、NOTCH 3表达和LADC TIC行为中的作用; 2）评估PKC 1-ELF 3-NOTCH 3信号传导轴在突变型Kras介导的肺肿瘤起始和进展中的作用;和3）评估新型高效和选择性PKC 1抑制剂作为治疗KRAS LADC的治疗策略的潜力。这些目标的成功完成将：1）提供对新鉴定的PKC 1-ELF 3-N 0 TCH 3信号传导轴的新的机制见解; 2）评估该途径在维持LADC TIC表型中的重要性; 3）鉴定PKC 1-ELF 3依赖性转录调节的新靶标; 4）评估PKC 1-ELF 3-N 0 TCH 3信号传导轴在LADC肿瘤起始和维持中的重要性;和5）评估新开发的高效PKC 1抑制剂在治疗KRAS LADC中的效用。鉴于KRAS LADC患者的临床结局较差，且缺乏治疗选择，这些研究可能对这些患者的临床管理产生广泛影响。

 DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the US, exhibiting a dismal five year survival rate of ~16%, underscoring the need for new therapeutic approaches. The recent development of targeted therapeutics that effectively treat lung cancer subtypes harboring specific driver mutations in EGFR, MET and EML4-ALK have made important inroads in treating these specific subsets of lung cancer. Despite these key advances, treatment options for mutant KRAS-driven lung adenocarcinoma (KRAS LADC), the most prevalent form of lung cancer, remain limited. We have identified protein kinase Cι (PKCι) as an oncogene in KRAS LADC and lung squamous cell carcinoma (LSCC), the two major forms of non-small cell lung cancer (NSCLC). PKCι functions to maintain a tumor-initiating cell (TIC) phenotype in both of these NSCLC tumor types. Surprisingly however, our published and preliminary studies demonstrate that PKCι drives a TIC phenotype in KRAS LADC and LSCC through distinct signaling pathways. Preliminary data demonstrate that: 1) PKCι drives a KRAS LADC TIC phenotype by activating expression of the pluripotent stem factor NOTCH3; 2) PKCι activates NOTCH3 expression by recruiting the ELF3 transcription factor to the NOTCH3 promoter; 3) PKCι phosphorylates ELF3 at Ser68 to regulate ELF3 occupancy and activation of the NOTCH3 promoter; 4) a newly identified, highly potent and selective PKCι inhibitor inhibits LADC TIC cell behavior in vitro. Based on these data, we hypothesize that: 1) PKCι regulates ELF3 promoter occupancy on NOTCH3 and other gene targets involved in maintaining a LADC TIC phenotype; 2) the novel PKCι-ELF3-NOTCH3 signaling axis drives Kras-mediated LADC initiation and progression in mouse models of Kras LADC; 3) our novel, potent and highly selective PKCι inhibitor will exhibit anti-tumor activity in KRAS LADC, and PKCι-ELF3-NOTCH3 signaling intermediates will be useful predictive and pharmacodynamic biomarkers of response. These hypotheses will be tested in three interrelated specific aims to: 1) assess the role of PKCι-mediated ELF3 phosphorylation in NOTCH3 promoter occupancy, NOTCH3 expression and LADC TIC behavior; 2) assess the role of the PKCι- ELF3-NOTCH3 signaling axis in mutant Kras-mediated lung tumor initiation and progression; and 3) assess the potential of a novel highly potent and selective PKCι inhibitor as a therapeutic strategy for treatment of KRAS LADC. Successful completion of these aims will: 1) provide new mechanistic insight into the newly- identified PKCι-ELF3-NOTCH3 signaling axis; 2) assess the importance of this pathway in the maintenance of a LADC TIC phenotype; 3) identify novel targets for PKCι-ELF3-dependent transcriptional regulation; 4) assess the importance of the PKCι-ELF3-NOTCH3 signaling axis in LADC tumor initiation and maintenance; and 5) assess the utility of a newly-developed, highly potent PKCι inhibitor in the treatment of KRAS LADC. Given the poor clinical outcome of patients with KRAS LADC, and the dearth of therapeutic options, these studies may have widespread impact on the clinical management of these patients.