Assessing BIM expression as a cause and marker for resistance to targeted therapi

描述(申请人提供)：在过去的几年里，我们了解到，在基因定义的癌症亚群中，它们的生长和生存需要激活的激酶。在这些癌症中，激酶通常由基因改变、突变、扩增或易位直接激活。这些癌细胞对基因激活的激酶“上瘾”，一旦该激酶被抑制，它们就会通过细胞凋亡而死亡。这就是所谓的“靶向治疗”。这些发现已经对癌症治疗产生了革命性的影响。2009年，马萨诸塞州总医院(MGH)创建了一个转化研究实验室，对在MGH接受治疗的所有患者的肺癌进行多重基因分析，在过去一年中，我们已经对600多例患者进行了基因分型。这项技术正迅速在全国许多其他癌症中心实施，突显了这一新兴领域的重要性。有趣的是，虽然许多这些基因定义的癌症(如EGFR突变和ALK易位)在靶向治疗后有戏剧性的反应，但有些要么反应差，要么没有反应，原因很不清楚。虽然其中一些癌症的耐药性被认为是由继发性突变引起的，这些突变导致在靶向治疗存在的情况下持续的细胞内信号传递，但大量的人群 在癌症中没有携带这些突变的患者，由于未知的原因而产生抗药性。我们发现，当靶向治疗同时导致生长停滞和细胞死亡(细胞凋亡)时，效果最好。当他们未能做到这一点时，回应就会得到缓解。诱导细胞凋亡的靶向治疗不足可能是由于促凋亡蛋白BIM缺乏所致。在本申请中，我们提出，在癌基因成瘾的背景下， 当靶向治疗不能诱导癌基因成瘾癌症患者的细胞凋亡时，就会产生耐药性，尽管细胞内信号转导下调，并假定这些癌症不能 由于BIM表达不足，导致细胞发生凋亡。我们强调了支持这些假说的初步数据，包括体外和体内的功能分析，预测 在细胞系模型中，BIM表达对细胞凋亡的能力，以及患者数据表明，BIM表达可以前瞻性地预测患者对EGFR突变靶向治疗的反应。最后，我们讨论了潜在的，可测试的药物策略，以克服这些癌症中的BIM缺陷。如果我们的可检验假设被证明是正确的，那么确定癌基因成瘾癌症治疗前水平的BIM表达将改变这一不断增长的癌症患者的治疗方式。

DESCRIPTION (provided by applicant): Over, the past several years, we have learned that subsets of genetically defined cancers require an activated kinase for their growth and survival. In these cancers, the kinase is often directly activated by genetic alteration; mutation, amplification or translocation. These cancer cells are "addicted" to the genetically activated kinase, and they die, via apoptosis, upon inhibition of the kinase. This is known as "targeted therapy." These findings have already had a transformative impact on cancer therapeutics. In 2009, Massachusetts General Hospital (MGH) created a Translational Research Laboratory to perform multiplexed genetic analyses on the lung cancers of all patients being treated at MGH, and we have genotyped over 600 cases in the past year. This technology is quickly being implemented at many other cancer centers throughout the country, highlighting the importance of this burgeoning field. Intriguingly, while many of these genetically defined cancers (such as EGFR mutant and ALK translocated) have dramatic responses following targeted therapies, some have either poor responses or no responses, for largely unknown reasons. While resistance in some of these cancers are thought to be caused by secondary mutations that result in sustained intracellular signaling in the presence of targeted therapy, a large population of patients, whom do not carry these mutations in their cancers, are resistant for unknown reasons. We have found that targeted therapies are most effective when they induce both growth arrest and cell death (apoptosis). When they fail to, responses are mitigated. The inadequacy of targeted therapies to induce apoptosis may be caused by a deficiency in the pro-apoptotic protein, BIM. In this application, we propose that, in the setting of oncogene addiction, resistance arises when targeted therapies fail to induce apoptosis in oncogene-addicted cancers, despite downregulation of the intracellular signaling and posit that these cancers fail to undergo apoptosis because of deficiencies in the expression of BIM. We highlight preliminary data that supports these hypotheses, including functional in vitro and in vivo analyses, predictive power of BIM expression to apoptosis in cell line models, and patient data suggesting BIM expression can prospectively predict patient response to EGFR mutant targeted therapies. Lastly, we discuss potential, testable pharmaceutical strategies to overcome BIM deficiency in these cancers. If our testable hypothesis is proven correct, determining BIM expression in pre-treatment levels of oncogene- addicted cancers will change the way this growing population of cancer patients is treated.