Understanding intrinsic resistance to direct KRAS inhibition in colorectal cancers
了解结直肠癌对直接 KRAS 抑制的内在抵抗
基本信息
- 批准号:10346971
- 负责人:
- 金额:$ 52.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AXIN2 geneBRAF geneCRISPR interferenceCTNNB1 geneCancer BiologyCancer EtiologyCancer ModelCell Culture TechniquesCell LineCell ProliferationCellsCessation of lifeCholangiocarcinomaClinical DataClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsColorectalColorectal CancerComplexDataDependenceDevelopmentDown-RegulationDrug CombinationsDrug resistanceEngineeringExposure toFeedbackGene ExpressionGenesGenetic TranscriptionGenomic approachHumanIn VitroIndividualInferiorKRAS oncogenesisKRAS2 geneLGR5 geneLaboratoriesLinkMalignant NeoplasmsMalignant neoplasm of lungMapsMediator of activation proteinMitogen-Activated Protein KinasesModelingMutationNon-Small-Cell Lung CarcinomaOncogenesOncogenicOrganoidsOutcomeOutputPIK3CA genePancreatic Ductal AdenocarcinomaPathway interactionsPatientsPharmaceutical PreparationsPhosphotransferasesPorcupinesProteomicsRecurrenceRefractoryRegimenRegulationResistanceRoleSignal TransductionSkinTankyraseTestingTissuesToxic effectTranslationsTumor Cell LineUnited StatesWNT Signaling PathwayWorkbasecancer cellcancer genomicscolon cancer cell linecolon cancer patientscolorectal cancer treatmentfunctional genomicsgenomic dataimprovedin vivoinhibitorinterestknock-downmelanomametastatic colorectalmutantnew technologynovel strategiesnovel therapeuticspatient derived xenograft modelpatient populationprogramsresistance mechanismresponsesmall moleculesmall molecule inhibitorsystemic toxicitytargeted agenttargeted treatmenttooltranscription factortreatment strategytumortumor growth
项目摘要
PROJECT SUMMARY/ABSTRACT
Metastatic colorectal cancers (CRC) are the second leading cause of cancer death in the US. While advances
in targeted therapies have transformed the treatment of many cancers, CRC has proven largely refractory to this
approach. Thus, while agents targeting BRAFV600E and the KRASG12C mutation have dramatically improved the
treatment of lung cancer and melanoma, they have only shown limited impact in CRC.
CTNNB1 transcription is upregulated in >75% of CRC via APC inactivation and other mutations. As CTNNB1 is
a common mediator of drug resistance and has been shown to be sufficient to maintain CRC proliferation, we
hypothesize that it is a key mediator of intrinsic resistance to KRAS inhibition in CRC. Although multiple agents
target CTNNB1 regulation via the WNT pathway, these have proven too toxic for human use to date.
Thus, we have used proteomics to map the signaling response to KRASG12C inhibition in CRC cell lines and
kinome-wide knockdown to identify kinases whose suppression synergizes with KRASG12C inhibition. By
integrating these two approaches, we were able to uncover several kinases that function as signaling links
between KRAS and CTNNB1, and whose inhibition synergizes with direct KRAS inhibition to reduce CTNNB1
target gene expression. As KRASG12C inhibitors do not impact normal KRAS signaling, this exciting preliminary
data suggests that we may be able to preferentially downregulate CTNNB1 in tumors without systemic toxicity.
We will build on this key preliminary data in this project: In Aim 1, we will expand our analysis of the kinase
response to KRASG12C inhibition to additional CRC cell lines and the assess the impact of key kinases on
CTNNB1 transcription. In Aim 2, we will use CRISPR in patient-derived xenografts (PDX) to circumvent the
limitations of available small molecules to validate the role of CTNNB1 in APC-mutant CRC PDX. We will further
use CRISPR or small molecules (when available) to test kinases already found to modulate CTNNB1 or emerging
from Aim 1 in CRC treatment models and to determine their role in in vivo CRC biology. Finally, in Aim 3 we will
develop KRASG12C CRC organoid and cell line models with mutations in PIK3CA, a common CRC mutation that
co-occurs with KRAS mutations and is likely to cause resistance to KRASG12C inhibitors, but for which there are
no models currently available. These tools will allow us to stratify the impact of PIK3CA mutation on our current
treatment strategies and to optimize a regimen engineered specifically for this combination of mutations.
This rigorous study of KRAS-driven signaling in CRC leverages new small molecules and robust quantitative
approaches to unmask links between KRAS and the mechanisms that support CRC after KRAS inhibition.
Uncovering the basis of resistance to direct KRAS inhibition in CRC will yield rational combination strategies
primed for translation into clinical trials.
项目总结/摘要
转移性结直肠癌(CRC)是美国癌症死亡的第二大原因。虽然进步
靶向治疗已经改变了许多癌症的治疗,CRC已被证明在很大程度上对此难治。
approach.因此,尽管靶向BRAFV 600 E和KRASG 12 C突变的药剂显著改善了BRAFV 600 E的表达,但其在治疗中的作用仍然是显著的。
尽管它们用于肺癌和黑色素瘤的治疗,但它们在CRC中仅显示出有限的影响。
在>75%的CRC中,通过APC失活和其他突变,CTNNB 1转录上调。由于CTNNB 1是
一种常见的耐药性介质,并已被证明足以维持CRC增殖,我们
假设它是CRC中对KRAS抑制的内在抗性的关键介质。虽然多个代理商
通过WNT途径靶向CTNNB 1调节,迄今为止这些已被证明对人类使用毒性太大。
因此,我们已经使用蛋白质组学来绘制CRC细胞系中对KRASG 12 C抑制的信号应答,
全激酶组敲低以鉴定其抑制与KRASG 12 C抑制协同的激酶。通过
结合这两种方法,我们能够发现几种作为信号联系的激酶
在KRAS和CTNNB 1之间,并且其抑制与直接KRAS抑制协同作用以减少CTNNB 1
靶基因表达。由于KRASG 12 C抑制剂不影响正常的KRAS信号传导,因此这一令人兴奋的初步研究
数据表明我们可能能够优先下调肿瘤中的CTNNB 1而没有全身毒性。
在本项目中,我们将以这些关键的初步数据为基础:在目标1中,我们将扩展我们对激酶的分析,
KRASG 12 C抑制对其他CRC细胞系的反应,并评估关键激酶对
CTNNB 1转录。在目标2中,我们将在患者来源的异种移植物(PDX)中使用CRISPR来规避CRISPR。
可用小分子的局限性,以验证CTNNB 1在APC突变型CRC PDX中的作用。我们将进一步
使用CRISPR或小分子(如果可用)来测试已经发现调节CTNNB 1或新出现的激酶
从目标1中的CRC治疗模型,并确定其在体内CRC生物学中的作用。最后,在目标3中,
开发具有PIK 3CA突变的KRASG 12 C CRC类器官和细胞系模型,PIK 3CA是一种常见的CRC突变,
与KRAS突变共同发生,可能导致对KRASG 12 C抑制剂的耐药性,但
目前没有可用的模型。这些工具将使我们能够对PIK 3CA突变对我们目前的研究的影响进行分层。
治疗策略,并优化专门针对这种突变组合设计的方案。
这项对CRC中KRAS驱动的信号传导的严格研究利用了新的小分子和稳健的定量分析。
揭示KRAS与KRAS抑制后支持CRC的机制之间联系的方法。
揭示CRC对直接KRAS抑制耐药的基础将产生合理的组合策略
已经准备好进行临床试验了
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
John D Gordan其他文献
John D Gordan的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('John D Gordan', 18)}}的其他基金
Understanding intrinsic resistance to direct KRAS inhibition in colorectal cancers
了解结直肠癌对直接 KRAS 抑制的内在抵抗
- 批准号:
10542813 - 财政年份:2022
- 资助金额:
$ 52.64万 - 项目类别:
相似海外基金
BRAF gene mutation causes hallmarks of cancer associated with tumor microenvironment
BRAF基因突变导致与肿瘤微环境相关的癌症特征
- 批准号:
18K14582 - 财政年份:2018
- 资助金额:
$ 52.64万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Significance of BRAF gene mutation on tumor microenvironment
BRAF基因突变对肿瘤微环境的意义
- 批准号:
16K20968 - 财政年份:2016
- 资助金额:
$ 52.64万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Evaluation of radiation effect based on point mutation of BRAF gene
基于BRAF基因点突变的放射效果评价
- 批准号:
15K12202 - 财政年份:2015
- 资助金额:
$ 52.64万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Analysis of tumor clonality using SNPs surrounding BRAF gene and its association with clinicopathological features
BRAF基因周围SNP分析肿瘤克隆性及其与临床病理特征的关系
- 批准号:
19790651 - 财政年份:2007
- 资助金额:
$ 52.64万 - 项目类别:
Grant-in-Aid for Young Scientists (B)