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Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas
Genes ( IF 3.5 ) Pub Date : 2021-09-11 , DOI: 10.3390/genes12091402
Elisa Baldelli 1 , Emna El Gazzah 1, 2 , John Conor Moran 1 , Kimberley A Hodge 1 , Zarko Manojlovic 3 , Rania Bassiouni 3 , John D Carpten 3 , Vienna Ludovini 4 , Sara Baglivo 4 , Lucio Crinò 5 , Fortunato Bianconi 6 , Ting Dong 1 , Jeremy Loffredo 1 , Emanuel F Petricoin 1 , Mariaelena Pierobon 1, 2
Affiliation  

KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.

中文翻译:

野生型 KRAS 等位基因对 KRAS 突变肺腺癌药物靶点的影响

KRAS突变是非小细胞肺癌 (NSCLC) 尤其是肺腺癌中最常见的致癌驱动因素之一。开发针对 KRAS 的疗法极具挑战性,促使间接抑制 MEK 和 ERK 等下游靶标。不幸的是,这些抑制剂的临床疗效有限,因此对开发新的治疗策略的需求仍然是这些患者的迫切需求。探索野生型 (WT) KRAS对药物靶点的影响可以发现治疗KRAS突变肺腺癌的新漏洞。使用市售的KRAS突变肺腺癌细胞系,我们探索了 WT KRAS的影响关于信号网络和药物靶点。反相蛋白微阵列 (RPPA) 捕获了 183 种信号蛋白的表达和/或激活,其中大多数是 FDA 批准的药物的靶标。使用 RPPA 在 23 个外科生物样本的队列中验证了选定的发现。沿着 MAPK 和 AKT/mTOR 信号通路和细胞周期调节剂的改变检测到与KRAS WT 等位基因存在相关的激酶驱动特征。FoxM1 成为在细胞系和临床样本中保留KRAS WT 等位基因的肿瘤的潜在脆弱性。我们的研究结果表明,WT KRAS的缺失会影响KRAS突变肺腺癌中的信号传导事件和可药物靶点。
更新日期:2021-09-12
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