Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1.


:Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.


Cell Rep


Cell reports


Tajiri H,Uruno T,Shirai T,Takaya D,Matsunaga S,Setoyama D,Watanabe M,Kukimoto-Niino M,Oisaki K,Ushijima M,Sanematsu F,Honma T,Terada T,Oki E,Shirasawa S,Maehara Y,Kang D,Côté JF,Yokoyama S,Kanai M,Fukui Y




Has Abstract


2017-05-02 00:00:00












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    pub_type: 杂志文章


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    pub_type: 杂志文章


    authors: Lo KA,Labadorf A,Kennedy NJ,Han MS,Yap YS,Matthews B,Xin X,Sun L,Davis RJ,Lodish HF,Fraenkel E

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Serbanescu D,Ojkic N,Banerjee S

    更新日期:2020-09-22 00:00:00

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Rozen EJ,Roewenstrunk J,Barallobre MJ,Di Vona C,Jung C,Figueiredo AF,Luna J,Fillat C,Arbonés ML,Graupera M,Valverde MA,de la Luna S

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    journal_title:Cell reports

    pub_type: 杂志文章


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    journal_title:Cell reports

    pub_type: 杂志文章


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