The RAF/MEK clamp VS-6766 shows strong anti-tumor activity across multiple MAPK pathway alterations, with a preferential effect on KRAS G12V

克拉斯 神经母细胞瘤RAS病毒癌基因同源物 癌症研究 MEK抑制剂 MAPK/ERK通路 激酶 威罗菲尼 结直肠癌 癌症 医学 突变 V600E型 生物 内科学 黑色素瘤 遗传学 基因 转移性黑色素瘤
作者
Sílvia Coma,Mónica Musteanu,Alessia Mira,C. Caffarra,Deborah K. Morrison,Cristina Ambrogio,Mariano Barbacid,JA Pachter
出处
期刊:European Journal of Cancer [Elsevier BV]
卷期号:174: S18-S18
标识
DOI:10.1016/s0959-8049(22)00851-6
摘要

Background: KRAS is the most frequently mutated RAS/RAF family member (mutated in 15% of cancers), followed by BRAF (5%) and NRAS (3%). Several BRAF and MEK inhibitors (MEKi) are approved for BRAF V600E cancers, and the G12C inhibitor sotorasib is approved for KRAS G12C non-small cell lung cancer (NSCLC). However, there is still a need for agents targeting other RAS/RAF mutations (mt), including KRAS G12 V which is mutated in ∼7%, ∼9% and ∼19% of NSCLC, colorectal and pancreatic cancers, respectively. VS-6766 is a unique RAF/MEK clamp that potently inhibits MEK kinase activity and induces a dominant negative RAF-MEK complex preventing phosphorylation of MEK by ARAF, BRAF and CRAF. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory re-activation of MEK that appears to limit the efficacy of MEKi. Material and Methods: In vitro assays were performed to evaluate the anti-proliferative activity of VS-6766 in human tumor cell lines with MAPK pathway alterations and in RAS-less mouse embryonic fibroblasts (MEFs) stably transfected with various KRAS variants. The anti-tumor activity of VS-6766 was assessed in genetically engineered mouse models (GEMM) of KRAS G12 V/Trp53 KO and KRAS G12C/Trp53 KO NSCLC. Results: VS-6766 showed strong anti-proliferative potency across tumor cell lines carrying KRAS, BRAF, CRAF, NRAS or NF1 alterations. Among KRAS mt cell lines, the anti-proliferative potency of VS-6766 differed by KRAS variant, with greatest potency observed with G12 V > G12C > G12D, which is consistent with G12 V signaling through CRAF/MEK/ERK and G12D signaling more through PI3 K/AKT/mTOR. Similarly, in MEFs stably transfected with different KRAS variants, VS-6766 showed best potency with KRAS G12 V and G12C, and least potency with G12D and KRAS wildtype. Accordingly, in the KRAS G12 V NSCLC GEMM model, previously shown to be CRAF-dependent, VS-6766 monotherapy induced stronger tumor regression than in a corresponding G12C NSCLC GEMM model. Strikingly, the combination of VS-6766 with FAK inhibition conferred tumor regressions in 87% (27/31) and 71% (36/51) of all tumors in the KRAS G12 V and KRAS G12C NSCLC models, respectively. Clinically, objective responses to VS-6766 monotherapy occurred mainly in patients with KRAS G12 V with 4 out of the 7 responders bearing KRAS G12 V (Guo, 2020). In KRAS mt NSCLC patients treated with VS-6766 in combination with the FAK inhibitor defactinib, a G12 V preference was also observed with confirmed responses in 2/2 patients with KRAS G12 V and tumor reduction in 4/6 patients with KRAS G12C (Krebs, 2021). Conclusions: These data support the ongoing registration-directed study evaluating VS-6766 ± defactinib for patients with KRAS G12 V NSCLC (NCT04620330), as well as the clinical combinations of VS-6766 with the KRAS G12C inhibitors sotorasib (NCT05074810) or adagrasib (NCT05375994) for KRAS G12C NSCLC. No conflict of interest.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
sujustin333发布了新的文献求助10
1秒前
量子星尘发布了新的文献求助10
1秒前
高挑的寒松完成签到,获得积分10
2秒前
2秒前
阿M啊啊完成签到,获得积分10
3秒前
奇异喵完成签到,获得积分10
3秒前
hui完成签到,获得积分20
3秒前
SSS水鱼发布了新的文献求助30
5秒前
顺shun完成签到 ,获得积分10
5秒前
情怀应助huayi采纳,获得10
6秒前
djiwisksk66应助南佳采纳,获得10
6秒前
7秒前
Albertxkcj发布了新的文献求助10
7秒前
hui发布了新的文献求助10
7秒前
无花果应助奇异喵采纳,获得10
8秒前
8秒前
Gudeguy完成签到 ,获得积分10
10秒前
11秒前
11秒前
点点完成签到,获得积分10
12秒前
顺利纸飞机完成签到,获得积分10
12秒前
粽粽发布了新的文献求助20
13秒前
脑洞疼应助LL采纳,获得10
14秒前
无限的可乐完成签到,获得积分10
14秒前
orixero应助zhang005on采纳,获得10
15秒前
Orange应助leon采纳,获得10
15秒前
Lu发布了新的文献求助10
15秒前
cherry发布了新的文献求助10
17秒前
小二郎应助hui采纳,获得10
17秒前
Akim应助163采纳,获得10
17秒前
隐形曼青应助lcs24201002032采纳,获得10
17秒前
17秒前
xiangoak发布了新的文献求助20
18秒前
豆花发布了新的文献求助10
18秒前
田様应助ZCC采纳,获得10
19秒前
19秒前
20秒前
20秒前
斤斤发布了新的文献求助10
21秒前
hailey53完成签到,获得积分10
21秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
Cognitive Neuroscience: The Biology of the Mind 1000
Technical Brochure TB 814: LPIT applications in HV gas insulated switchgear 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Picture Books with Same-sex Parented Families: Unintentional Censorship 500
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3969557
求助须知:如何正确求助?哪些是违规求助? 3514377
关于积分的说明 11173836
捐赠科研通 3249692
什么是DOI,文献DOI怎么找? 1794979
邀请新用户注册赠送积分活动 875537
科研通“疑难数据库(出版商)”最低求助积分说明 804836