Mechanism-based strategies to target oncogenic BRAF signaling

针对致癌 BRAF 信号传导的基于机制的策略

• 批准号: 10053708
• 负责人: Poulikos I Poulikakos
• 金额: $ 38.79万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-08 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053708
• 关键词: Allosteric Regulation; Ally; Area; BRAF gene; Binding; Biochemical; Biological Assay; Cell Line; Cells; Clinical; Colorectal; Complex; Data; Development; Dimerization; Drug Design; Drug Side Effects; Drug resistance; Effectiveness; Event; Goals; Human; In complete remission; Investigation; Knowledge; Link; MEKs; Mediating; Modeling; Molecular Conformation; Multi-Drug Resistance; Mutate; Mutation; Normal Cell; Oncogenic; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Property; Proto-Oncogene Proteins B-raf; Protomer; Ras/Raf; Recovery; Regulation; Reporting; Resistance; Resistance development; Signal Transduction; Site; Structure; Testing; Therapeutic; Thyroid Gland; Time; Work; Xenograft procedure; acquired drug resistance; base; biophysical techniques; cell growth; clinical development; clinical efficacy; comparative efficacy; design; dimer; effective therapy; experimental study; improved; in vivo; inhibitor/antagonist; insight; melanoma; mutant; next generation; preclinical development; resistance mechanism; response; side effect; small molecule inhibitor; targeted treatment; therapeutically effective; tumor

Abstract BRAF kinase is frequently found mutated in human tumors and in the majority of melanomas. RAF inhibitors vemurafenib and dabrafenib improved survival of melanoma patients with BRAF(V600E) tumors. Unfortunate- ly, responses are usually temporary, followed by development of resistance, most commonly due to ineffective inhibition of RAF and reactivation of ERK signaling in the presence of the drug. In addition, RAF inhibitors in- duce second site tumors, due to RAS-dependent paradoxical activation of RAF and downstream ERK signaling in normal cells. Outside of melanoma, RAF inhibitors showed limited efficacy in patients colorectal and thyroid BRAF(V600E) tumors, also due to ineffective inhibition of RAF/ERK signaling in these tumors. More recently, combinations of RAF and MEK inhibitors showed improved efficacy compared to RAF inhibitor monotherapy, but resistance eventually emerges as well. Resistance mechanisms identified to the RAF/MEK inhibitor combi- nation are similar to the ones identified for RAF inhibitor monotherapy, suggesting that ineffective inhibition of RAF is a critical limiting factor in both contexts. There is thus a pressing need for improved therapeutic strate- gies targeting oncogenic BRAF, such that durable responses and minimal side effects can be achieved. Our previous work showed that regulation of BRAF kinase by dimerization determines both the development of re- sistance to currently used RAF inhibitors and inhibitor-induced RAF paradoxical activation, but the underlying mechanisms remain incompletely understood. Recently, next generation RAF inhibitors with different structural and biochemical properties have entered preclinical and clinical development, but the most appropriate clinical context for their use is unknown. The goal of this proposal is to accomplish a detailed understanding of the mechanisms governing the targeting of oncogenic BRAF by small molecules inhibitors and to use this knowledge in order to design more effective RAF inhibitor-based therapeutic strategies. More specifically, we will 1) characterize the mechanistic basis of resistance to RAF inhibitors due to BRAF dimerization by linking the conformational changes induced by inhibitor binding to BRAF to the biochemical effects of the inhibitor, 2) gain a detailed understanding of the biochemical mechanism of paradoxical RAF activation by inhibitors in cells with wild-type BRAF and 3) identify effective RAF inhibitor-based therapeutic strategies for tumors with dimeric BRAF that would overcome RAF dimer-mediated intrinsic or acquired resistance to RAF inhibitors. The mech- anistic insights gained by the proposed experiments will enable the rational design of more effective small mol- ecule inhibitors and RAF inhibitor-based therapeutic strategies targeting oncogenic BRAF signaling, with mini- mal side effects and prolonged time to resistance.

抽象的 在人类肿瘤和大多数黑色素瘤中经常发现BRAF激酶。 RAF抑制剂 vemurafenib和dabrafenib改善了黑色素瘤患者BRAF（V600E）肿瘤的存活率。不幸- ly，反应通常是暂时的，其次是抗性的，最常见的是由于无效 在药物存在下抑制RAF和ERK信号的重新激活。此外，RAF抑制剂In- Duce第二位点肿瘤，由于RAS依赖性矛盾激活RAF和下游ERK信号传导 在正常细胞中。在黑色素瘤之外，RAF抑制剂对患者结肠直肠和甲状腺的疗效有限 BRAF（V600E）肿瘤，也是由于这些肿瘤中RAF/ERK信号的抑制无效。最近， 与RAF抑制剂单一疗法相比 但是抵抗最终也出现了。识别为RAF/MEK抑制剂组合的耐药机制 民族与RAF抑制剂单一疗法确定的国家相似，表明对 RAF在这两种情况下都是关键的限制因素。因此，紧迫的需要改善治疗策略 靶向致癌BRAF的GIE，从而可以实现持久的反应和最小的副作用。我们的 先前的工作表明，通过二聚化对BRAF激酶的调节决定了重新的发展 当前使用RAF抑制剂和抑制剂诱导的RAF矛盾激活的含量，但基础 机制仍然不完全理解。最近，具有不同结构的下一代RAF抑制剂 生化特性已进入临床前和临床发育，但最合适的临床 他们使用的上下文未知。该提案的目的是完成对 由小分子抑制剂控制致癌BRAF的机制，并使用 知识以设计更有效的RAF抑制剂治疗策略。更具体地说，我们 会1）表征由于BRAF二聚体而引起的对RAF抑制剂的抗性的机理基础 抑制剂与BRAF与抑制剂的生化作用结合引起的构象变化，2） 详细了解细胞中抑制剂的矛盾RAF激活的生化机制 使用野生型BRAF和3）确定具有二聚体肿瘤的有效基于RAF抑制剂的治疗策略 将克服RAF二聚体介导的内在或获得对RAF抑制剂的耐药性的BRAF。机甲 - 提出的实验获得的无态见解将使更有效的小分子的合理设计 针对致癌BRAF信号的ecule抑制剂和基于RAF抑制剂的治疗策略，微型 Mal副作用和持续时间延长。

项目成果

ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation.

• DOI: 10.1038/s41467-022-28319-3
• 发表时间: 2022-02-04
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Esposito D;Pant I;Shen Y;Qiao RF;Yang X;Bai Y;Jin J;Poulikakos PI;Aaronson SA
• 通讯作者: Aaronson SA

Mouse ER+/PIK3CAH1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents.

由外源雌激素引起的小鼠 ER /PIK3CAH1047R 乳腺癌对雌激素具有异质依赖性，并在 BH3 和 PI3K 药物的作用下经历 BIM 依赖性细胞凋亡。

• DOI: 10.1038/s41388-018-0436-4
• 发表时间: 2019
• 期刊: Oncogene
• 影响因子: 8
• 作者: Stratikopoulos,EliasE;Kiess,Nicole;Szabolcs,Matthias;Pegno,Sarah;Kakit,Cheung;Wu,Xuewei;Poulikakos,PoulikosI;Cheung,Pamela;Schmidt,Hank;Parsons,Ramon
• 通讯作者: Parsons,Ramon

New perspectives for targeting RAF kinase in human cancer.

• DOI: 10.1038/nrc.2017.79
• 发表时间: 2017-11
• 期刊: Nature reviews. Cancer
• 作者: Karoulia Z;Gavathiotis E;Poulikakos PI
• 通讯作者: Poulikakos PI

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 2nd - 4th, 2021, Italy).

• DOI: 10.1186/s12967-022-03592-4
• 发表时间: 2022-09-04
• 期刊: JOURNAL OF TRANSLATIONAL MEDICINE
• 影响因子: 7.4
• 作者: Ascierto, Paolo A.;Agarwala, Sanjiv S.;Blank, Christian;Caraco, Corrado;Carvajal, Richard D.;Ernstoff, Marc S.;Ferrone, Soldano;Fox, Bernard A.;Gajewski, Thomas F.;Garbe, Claus;Grob, Jean-Jacques;Hamid, Omid;Krogsgaard, Michelle;Lo, Roger S.;Lund, Amanda W.;Madonna, Gabriele;Michielin, Olivier;Neyns, Bart;Osman, Iman;Peters, Solange;Poulikakos, Poulikos, I;Quezada, Sergio A.;Reinfeld, Bradley;Zitvogel, Laurence;Puzanov, Igor;Thurin, Magdalena
• 通讯作者: Thurin, Magdalena

Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation.

• DOI: 10.1186/s13045-022-01330-3
• 发表时间: 2022-08-17
• 期刊: JOURNAL OF HEMATOLOGY & ONCOLOGY
• 影响因子: 28.5
• 作者: Elnaggar, Muhammad;Agte, Sarita;Restrepo, Paula;Ram, Meghana;Melnekoff, David;Adamopoulos, Christos;Stevens, Mark M.;Kappes, Katerina;Leshchenko, Violetta;Verina, Daniel;Jagannath, Sundar;Poulikakos, Poulikos, I;Parekh, Samir;Lagana, Alessandro
• 通讯作者: Lagana, Alessandro