Targeting the ERK Pathway in KRAS-and BRAF-Driven Lung Cancers

突变的BRAF或突变的KRAS的肿瘤依赖ERK信号，并对MEK抑制剂敏感， 但只有BRAF突变的肿瘤对RAF抑制剂敏感。我们已经证明了RAF抑制剂 在大多数正常和肿瘤细胞中变构激活依赖于RAS的F？AF二聚体，因此矛盾地 激活信号。然而，在具有V600E BRAF突变的肿瘤中，激活的ERK会导致反馈抑制 RAS.GTP的水平太低，不能支持RAF二聚化，在此上下文中，V600E信号作为 单体。RAF抑制剂与单体结合，在这些肿瘤中有效地抑制ERK信号转导。这是 密码子600BRAF突变的黑色素瘤对这些药物显着疗效的基础 与MEK抑制剂相比。然而，肿瘤的反应是不完全的，而且往往是暂时的。肿瘤 进展是由于获得性抗性，其特征通常是ERK信号对RAF不敏感 抑制剂。我们已经证明，这可能是通过诱导RAS.GTP或剪接RAF的变体来实现的 以独立于RAS的方式进行二聚化。我们还认为，原始肿瘤的反应受到以下因素的限制 肿瘤对ERK抑制的适应性。在RAS和BRAF突变肿瘤中，ERK激活导致 反馈抑制其他细胞内信号通路，使细胞依赖ERK 发信号。这会导致对RAF抑制剂(突变型BRAF肿瘤)或MEK抑制剂(突变型 BRAF和一些KRAS肿瘤)。然而，用这些药物抑制ERK信号可以缓解这种情况 反馈，减弱ERK输出的抑制，并激活其他导致有丝分裂的信号通路 对ERK抑制的适应性抵抗。我们在这项提案中的目标是开发出最大限度地 通过将RAF或MEK抑制剂与选择性的MEK和RTK抑制剂相结合来抑制ERK输出，从而防止 皇家空军的反馈重新激活。我们假设，这些方案对ERK输出的最大抑制 将解除受体酪氨酸激酶信号的反馈抑制，并以这种方式引起耐药性。我们 将识别这些重新激活的通路，然后开发和测试基于最大ERK的治疗方法 抑制结合关键的反应性受体，以防止或限制适应性抵抗。

Tumors with mutant BRAF or mutant KRAS are dependent on ERK signaling and sensitive to MEK inhibitors, but only the BRAF mutant tumors are sensifive to RAF inhibitors. We have shown that RAF inhibitors allosterically activate RAS-dependent F?AF dimers in most normal and tumor cells and thus paradoxically acfivate signaling. However, in tumors with V600E BRAF mutafion, activated ERK causes feedback inhibition of RAS.GTP to a levels too low to support RAF dimerization and in this context V600E signals as a monomer. RAF inhibitors bind to the monomer and potently inhibit ERK signaling in these tumors. This is basis for the dramafic therapeutic response of melanomas with codon 600 BRAF mutafion to these drugs compared to MEK inhibitors. However, tumor responses are incomplete and often temporary. Tumor progression is due to acquired resistance often characterized by insensitivity of ERK signaling to the RAF inhibitor. We have shown that this may be mediated by inducfion of RAS.GTP or to splice variants of RAF that dimerize in a Ras-independent manner. We also believe that the inifial tumor response is limited by adaptafion of the tumor to inhibifion of ERK. In RAS and BRAF mutant tumors, ERK acfivation causes the feedback inhibition of other intracellular signaling pathways and renders the cell dependent on ERK signaling. This causes hypersensitivity to RAF inhibitors (mutant BRAF tumors) or MEK inhibitors (mutant BRAF and some KRAS tumors). However, inhibition of ERK signaling with these drugs relieves this feedback, attenuates inhibifion of ERK output, and acfivates other mitogenic signaling pathway that cause adaptive resistance to ERK inhibifion. Our goals in this proposal are to develop therapies that maximally inhibit ERK output by combining RAF or MEK inhibitors with selective MEK and RTK inhibitors that prevent feedback reactivation of RAF. We hypothesize that maximal inhibition of ERK output with these regimens will relieve feedback inhibition of receptor tyrosine kinase signaling and cause resistance in that manner. We will identify these reactivated pathways and then develop and test therapies based on maximal ERK inhibifion combined with inhibifion of key reacfivated receptors to prevent or limit adaptive resistance.