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

具有突变型BRAF或突变型KRAS的肿瘤依赖于ERK信号传导并且对MEK抑制剂敏感， 但只有BRAF突变型肿瘤对RAF抑制剂敏感。我们已经证明RAF抑制剂 变构激活RAS依赖的F？AF二聚体在大多数正常和肿瘤细胞，因此矛盾 激活信号传导。然而，在V600 E BRAF突变的肿瘤中，激活的ERK引起反馈抑制， GTP的水平太低而不能支持RAF二聚化，并且在这种情况下，V600E信号作为RAF二聚化的信号。 单体的RAF抑制剂与单体结合并有效抑制这些肿瘤中的ERK信号传导。这是 密码子600 BRAF突变的黑色素瘤对这些药物的戏剧性治疗反应的基础 与MEK抑制剂相比。然而，肿瘤反应是不完全的，而且往往是暂时的。肿瘤 进展是由于获得性耐药，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RAF的剪接变体介导的 以Ras独立的方式二聚化。我们还认为，初始肿瘤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突变型肿瘤中，ERK激活导致肿瘤细胞凋亡。 反馈抑制其他细胞内信号通路，使细胞依赖ERK 发信号。这导致对RAF抑制剂（突变型BRAF肿瘤）或MEK抑制剂（突变型BRAF肿瘤）的超敏反应。 BRAF和一些KRAS肿瘤）。然而，用这些药物抑制ERK信号传导可以缓解这种情况。 反馈，减弱ERK输出的抑制，并激活其他促有丝分裂信号通路， 对ERK抑制的适应性抗性。我们在这个提案中的目标是开发最大限度地 通过将RAF或MEK抑制剂与选择性MEK和RTK抑制剂组合来抑制ERK输出， 反馈激活RAF。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传导的反馈抑制并以该方式引起抗性。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的疗法。 抑制与抑制关键的再活化受体相结合以防止或限制适应性抗性。

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.