Dataset Information

Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders

ABSTRACT: CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Li Wang

LAB HEAD: Poulikos Poulikakos

PROVIDER: PXD023137 | Pride | 2022-02-16

REPOSITORIES: Pride

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			Action	DRS
	20181004_JinJ_ctrl_1.raw	Raw
	20181004_JinJ_ctrl_1_20181005040704.raw	Raw
	20181004_JinJ_ctrl_2.raw	Raw
	20181004_JinJ_ctrl_2_20181005102542.raw	Raw
	20181011_JinJ_140_11.raw	Raw

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Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders.

Wu Xuewei X Yang Xiaobao X Xiong Yan Y Li Ruitong R Ito Takahiro T Ahmed Tamer A TA Karoulia Zoi Z Adamopoulos Christos C Wang Hong H Wang Li L Xie Ling L Liu Jing J Ueberheide Beatrix B Aaronson Stuart A SA Chen Xian X Buchanan Sean G SG Sellers William R WR Jin Jian J Poulikakos Poulikos I PI

Nature cancer 20210301 4

CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly the ...[more]

PMID: 34568836

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Project description:Cdk4 and Cdk6 are two related kinases that bind D-type cyclins and regulate cell cycle progression. Due to their relevance in cancer, Cdk4/6 inhibitors are currently in advanced clinical trials in multiple tumor types. Cdk4/6 are inhibited by INK4 proteins that exert tumor suppressing functions. To test the significance of this inhibitory mechanism we have generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4-mediated inhibition. Cdk6R/R mice display altered development of the hematopoietic system without resulting in enhanced tumor susceptibility, either in the presence or absence of p53. The presence of the Cdk6 R31C allele results in defective potential of hematopoietic progenitors in adoptive transfer assays or after induced damage. These defects are rescued after complete insensitivity to INK4 inhibitors in Cdk4R/R; Cdk6R/R double mutant mice, and INK4-resistant mice display increased susceptibility to hematopoietic and endocrine tumors. In BCR-ABL-transformed hematopoietic cells, the presence of the Cdk6 R31C allele results in increased binding of p16INK4a to wild-type Cdk4, whereas the double mutant is fully insensitive to INK4 inhibitors resulting in accelerated disease onset. Our observations reveal that Cdk4 and Cdk6 cooperate in tumor development and suggest a role for Cdk6 in buffering INK4 protein levels thus contributing to the development of hematopoietic tumors. The presence of the Cdk4 R24C and Cdk6 R31C alleles results in relevant changes in the expression profiles of cancer cells including deregulation of apoptosis and other processes. p185BCR-ABL1 was used to transform wild-type or double knock-in Cdk4 R24C; Cdk6 R31C fetal livers. Cell lines were isolated as spontaneous immortal and transformed clones after transduction of fetal liver with a p185 BCR-ABL1-transgene. RNA was isolated from asynchronous cultures. Two-condition experiment, Cdk4R-Cdk6R cells versus wild-type cells. Biological replicates: 3 control replicates, 3 transfected replicates.