课题基金 / 基金详情

Dissecting KRAS oncoprotein signaling with small molecule inhibitors

Dissecting KRAS oncoprotein signaling with small molecule inhibitors
用小分子抑制剂剖析 KRAS 癌蛋白信号传导
批准号:
10659617
负责人:
Piro Lito
金额:
$44.25万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-09-01 至 2028-08-31

项目摘要

项目成果

Piro Lito的其他基金

相关文献

中文摘要
翻译
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT Small GTPases regulate diverse cellular functions and their aberrant activation plays a key role in disease. Perhaps most significant is their association with cancer, a disease where KRAS is mutated in ~1/3 of patients. With this in mind, the mechanism by which cancer hotspot mutations activate KRAS is a central concept in cancer biology. Under physiologic conditions, KRAS cycles between an active (GTP-bound) and an inactive (GDP-bound) conformation. Its slow intrinsic GTP hydrolysis is catalyzed by GTPase-activating proteins (GAPs). Common mutations in KRAS prevent the stabilization of the hydrolysis transition-state leading to oncoproteins that are thought to be deficient in hydrolysis, insensitive to GAPs, and constitutively active in cancer cells (i.e., `locked' in their active or GTP-bound, state). Emerging therapies are challenging the conventional model of KRAS oncoprotein activation. Perhaps the strongest evidence is provided by inhibitors selectively targeting KRAS G12C, the most common KRAS mutation in lung cancer. G12C inhibitors bind only to the GDP-bound (or hydrolyzed) conformation and trap the oncoprotein in an inactive state by preventing the exchange of GDP for GTP. To be effective, these inactive state selective drugs require intact GTP hydrolysis by mutant KRAS. In a similar fashion, inhibition of nucleotide-exchange (as achieved by targeting factors upstream of KRAS) has been reported to suppress mutant KRAS activation and/or tumor growth. This and other emerging therapeutic effects presented in the preliminary data of this application could not be possible if mutant KRAS GTPases were `locked' in their active state. Our proof-of-principle experiments suggest the presence of cellular proteins that enhance the GTPase activity of mutant KRAS and that KRAS oncoproteins are broadly susceptible to inactive state selective inhibition. We now propose (i) to isolate enhancers of mutant KRAS GTPase activity in cancer cells, (ii) to determine the tertiary structure of common KRAS mutants in complex with their enhancer and (iii) to characterize the effects of novel inactive state selective drugs that suppress common KRAS mutants found in cancer. This work will explain the mechanistic basis responsible for the physiologic inactivation of mutant KRAS and refine the conceptual model explaining how mutations activate KRAS in cancer. The proposed study will pave the way for key advances in cancer biology with a large potential for therapeutic and translational impact in patients.
期刊论文(18)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1158/1078-0432.ccr-20-4023
发表时间: 2021-04-15
期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子: --
作者: [Arbour KC, Rizvi H, Plodkowski AJ, Hellmann MD, Knezevic A, Heller G, Yu HA, Ladanyi M, Kris MG, Arcila ME, Rudin CM, Lito P, Riely GJ]
通讯作者: Riely GJ
DOI: 10.1016/j.cell.2020.09.044
发表时间: 2020-11-12
期刊: Cell
影响因子: 64.5
作者: [Kim D, Xue JY, Lito P]
通讯作者: Lito P
Suppressing Nucleotide Exchange to Inhibit KRAS-Mutant Tumors.
抑制核苷酸交换以抑制 KRAS 突变肿瘤。
DOI: 10.1158/2159-8290.cd-20-1331
发表时间: 2021
期刊: Cancer discovery
影响因子: 28.2
作者: [Zhao,Yulei, Xue,JennyY, Lito,Piro]
通讯作者: Lito,Piro
Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.
晚期非小细胞肺癌中循环肿瘤DNA引导的疗法的总生存期。
DOI: 10.1038/s41591-022-02047-z
发表时间: 2022-11
期刊: NATURE MEDICINE
影响因子: 82.9
作者: [Jee, Justin, Lebow, Emily S., Yeh, Randy, Das, Jeeban P., Namakydoust, Azadeh, Paik, Paul K., Chaft, Jamie E., Jayakumaran, Gowtham, Brannon, A. Rose, Benayed, Ryma, Zehir, Ahmet, Donoghue, Mark, Schultz, Nikolaus, Chakravarty, Debyani, Kundra, Ritika, Madupuri, Ramyasree, Murciano-Goroff, Yonina R., Tu, Hai-Yan, Xu, Chong-Rui, Martinez, Andres, Wilhelm, Clare, Galle, Jesse, Daly, Bobby, Yu, Helena A., Offin, Michael, Hellmann, Matthew D., Lito, Piro, Arbour, Kathryn C., Zauderer, Marjorie G., Kris, Mark G., Ng, Kenneth K., Eng, Juliana, Preeshagul, Isabel, Lai, W. Victoria, Fiore, John J., Iqbal, Afsheen, Molena, Daniela, Rocco, Gaetano, Park, Bernard J., Lim, Lee P., Li, Mark, Tong-Li, Candace, De Silva, Madhawa, Chan, David L., Diakos, Connie, I, Itchins, Malinda, Clarke, Stephen, Pavlakis, Nick, Lee, Adrian, Rekhtman, Natasha, Chang, Jason, Travis, William D., Riely, Gregory J., Solit, David B., Gonen, Mithat, Rusch, Valerie W., Rimner, Andreas, Gomez, Daniel, Drilon, Alexander, Scher, Howard, I, Shah, Sohrab P., Berger, Michael F., Arcila, Maria E., Ladanyi, Marc, Levine, Ross L., Shen, Ronglai, Razavi, Pedram, Reis-Filho, Jorge S., Jones, David R., Rudin, Charles M., Isbell, James M., Li, Bob T.]
通讯作者: Li, Bob T.
共 10 条
    Mechanisms of adaptation and resistance to emerging therapies for lung cancer
    Studies on the effects of a novel intermittent therapy on intratumoral clonal architecture and resistance
    Studies on the effects of a novel intermittent therapy on intratumoral clonal architecture and resistance
    Studies on the effects of a novel intermittent therapy on intratumoral clonal architecture and resistance