PXD023137

PXD023137 is an original dataset announced via ProteomeXchange.

Title	Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-02-16
AnnouncementXML	Submission_2022-02-16_10:37:56.427.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Li Wang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	carbamoylated residue; monohydroxylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-15 01:41:41	ID requested
⏵ 1	2022-02-16 10:37:57	announced

Wu X, Yang X, Xiong Y, Li R, Ito T, Ahmed TA, Karoulia Z, Adamopoulos C, Wang H, Wang L, Xie L, Liu J, Ueberheide B, Aaronson SA, Chen X, Buchanan SG, Sellers WR, Jin J, Poulikakos PI, Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders. Nat Cancer, 2(4):429-443(2021) [pubmed]

submitter keyword: CDK4/6 inhibitors and degraders, tumor, CDK6 complex

Poulikos Poulikakos
contact affiliation	Department of Oncological Sciences, Department of Dermatology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
contact email	poulikos.poulikakos@mssm.edu
lab head
Li Wang
contact affiliation	Postdoctoral Research Associate
contact email	liwang@email.unc.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/02/PXD023137

PRIDE project URI

• PRIDE
  1. PXD023137
     1. Label: PRIDE project
     2. Name: Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders