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000169929 0247_ $$2doi$$a10.1016/j.celrep.2021.109394
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000169929 0247_ $$2ISSN$$a2639-1856
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000169929 037__ $$aDKFZ-2021-01635
000169929 041__ $$aEnglish
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000169929 1001_ $$0P:(DE-He78)34c336827b750ba10a020fd62ec4664f$$aDieter, Sebastian$$b0$$eFirst author$$udkfz
000169929 245__ $$aDegradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer.
000169929 260__ $$a[New York, NY]$$bElsevier$$c2021
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000169929 520__ $$aNovel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of-but not all-spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.
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000169929 650_7 $$2Other$$aCCNK
000169929 650_7 $$2Other$$aCDK12
000169929 650_7 $$2Other$$acolorectal cancer
000169929 650_7 $$2Other$$amolecular glue degrader
000169929 650_7 $$2Other$$atargeted protein degradation
000169929 7001_ $$aSiegl, Christine$$b1
000169929 7001_ $$0P:(DE-He78)456affe157d8bee8a41108100e104e92$$aCodo, Paula Luciana$$b2
000169929 7001_ $$0P:(DE-HGF)0$$aHuerta, Mario$$b3
000169929 7001_ $$0P:(DE-He78)a27ddea8f7f0a3bace5e6a586a32279a$$aOstermann-Parucha, Anna Lena$$b4$$udkfz
000169929 7001_ $$aSchulz, Erik$$b5
000169929 7001_ $$aZowada, Martina K$$b6
000169929 7001_ $$0P:(DE-He78)5ef9ea2b7d03595663ed98fd407bba69$$aMartin, Sylvia$$b7$$udkfz
000169929 7001_ $$0P:(DE-He78)2edb00bc9fd4fe7c858c2838ce1c0024$$aLaaber, Karin$$b8$$udkfz
000169929 7001_ $$aNowrouzi, Ali$$b9
000169929 7001_ $$0P:(DE-He78)e60f04da55f0193520fabc5e75a1de8c$$aBlatter, Mona$$b10$$udkfz
000169929 7001_ $$0P:(DE-He78)21d657d65d4ad0fd8b0bbfe10fa65172$$aKreth, Sina$$b11$$udkfz
000169929 7001_ $$0P:(DE-He78)91f32735ee876c579d63c05a7f4778dd$$aWestermann, Frank$$b12$$udkfz
000169929 7001_ $$0P:(DE-He78)e15dfa1260625c69d6690a197392a994$$aBenner, Axel$$b13$$udkfz
000169929 7001_ $$aUhrig, Ulrike$$b14
000169929 7001_ $$aPutzker, Kerstin$$b15
000169929 7001_ $$aLewis, Joe$$b16
000169929 7001_ $$aHaegebarth, Andrea$$b17
000169929 7001_ $$aMumberg, Dominik$$b18
000169929 7001_ $$aHolton, Simon J$$b19
000169929 7001_ $$aWeiske, Joerg$$b20
000169929 7001_ $$aToepper, Lena-Marit$$b21
000169929 7001_ $$aScheib, Ulrike$$b22
000169929 7001_ $$aSiemeister, Gerhard$$b23
000169929 7001_ $$0P:(DE-He78)7a10ea1b9b2872da9f375002c44ddfce$$aBall, Claudia R$$b24$$udkfz
000169929 7001_ $$aKuster, Bernhard$$b25
000169929 7001_ $$aStoehr, Gabriele$$b26
000169929 7001_ $$aHahne, Hannes$$b27
000169929 7001_ $$aJohannes, Sarah$$b28
000169929 7001_ $$aLange, Martin$$b29
000169929 7001_ $$aHerbst, Friederike$$b30
000169929 7001_ $$0P:(DE-He78)157277fe62f07df1732f9d126a51d1b9$$aGlimm, Hanno$$b31$$udkfz
000169929 773__ $$0PERI:(DE-600)2649101-1$$a10.1016/j.celrep.2021.109394$$gVol. 36, no. 3, p. 109394 -$$n3$$p109394$$tCell reports$$v36$$x2211-1247$$y2021
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