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

突变的BRAF或突变的KRAS肿瘤依赖ERK信号，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，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，从而矛盾地激活信号。然而，在具有V600E BRAF突变的肿瘤中，激活的ERK导致RAS.GTP反馈抑制到太低的水平，以至于不能支持RAF二聚化，在这种情况下，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突变的黑色素瘤与MEK抑制剂相比对这些药物产生戏剧性治疗反应的基础。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耐药，其特征通常是ERK信号对RAF抑制剂不敏感。我们已经证明，这可能是通过诱导RAS.GTP或剪接以不依赖RAS的方式二聚化的RAF变体来介导的。我们还认为，肿瘤最初的反应受到肿瘤对ERK抑制的适应性的限制。在RAS和BRAF突变的肿瘤中，ERK的激活导致其他细胞内信号通路的反馈抑制，使细胞依赖于ERK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)的过敏。然而，用这些药物抑制ERK信号可以缓解这种反馈，减弱对ERK输出的抑制，并激活其他导致适应性抵抗ERK抑制的有丝分裂信号通路。我们在这项建议中的目标是开发通过将RAF或MEK抑制剂与选择性MEK和RTK抑制剂相结合来最大限度地抑制ERK输出的治疗方法，以防止RAF的反馈重新激活。我们假设，用这些方案最大限度地抑制ERK输出将解除对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。我们将确定这些重新激活的通路，然后开发和测试基于最大限度地抑制ERK和抑制关键的重新激活的受体来预防或限制适应性耐药的治疗方法。

Tumors with mutant BRAF or mutant KRAS are dependent on ERK signaling and sensitive to MEK inhibitors, but only the BRAF mutant tumors are sensitive 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 activate signaling. However, in tumors with V600E BRAF mutation, 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 dramatic therapeutic response of melanomas with codon 600 BRAF mutation 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 induction of RAS.GTP or to splice variants of RAF that dimerize in a Ras-independent manner. We also believe that the initial tumor response is limited by adaptation of the tumor to inhibition of ERK. In RAS and BRAF mutant tumors, ERK activation 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 inhibition of ERK output, and activates other mitogenic signaling pathway that cause adaptive resistance to ERK inhibition. 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 inhibition combined with inhibition of key reactivated receptors to prevent or limit adaptive resistance.