로그인
회원가입
Korean
Korean
English
Chinese
Japanese
Home
Introduction
Contact us
People
PI
Members
Research
Projects
Lab Facility
Publications
Papers
Books
Patents
Photo gallery
Photo gallery
Board
Projet update
Recruiting
Journal club
Home
People
Research
Publications
Photo gallery
Board
Home
Introduction
Contact us
People
PI
Members
Research
Projects
Lab Facility
Publications
Papers
Books
Patents
Photo gallery
Photo gallery
Board
Projet update
Recruiting
Journal club
MOON LAB SNS 바로가기
트위터
페이스북
네이버블로그
MOON LAB
홈페이지 바로가기
MOON LAB
Moon lab pursues development of novel therapeutics for breast, ovary, and prostate cancer
Journal club 글답변
이름
필수
비밀번호
필수
분류
선택하세요
Journal Club
Projet update
HTML
제목
필수
웹에디터 시작
> > > Date: 2021.09.14 > > Functional Determinants of Cell Cycle Plasticity and Sensitivity to CDK4/6 Inhibition > > Cancer Res. 2021 Mar 1;81(5):1347-1360. doi: 10.1158/0008-5472.CAN-20-2275. Epub 2020 Dec 15. > > Abstract > > Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors has emerged as a major obstacle that hinders their utility beyond ER+ breast cancer. In this study, CDK4/6-dependent and -resistant models were employed to identify functional determinants of response to pharmacologic CDK4/6 inhibitors. In all models tested, the activation of RB and inhibition of CDK2 activity emerged as determinants of sensitivity. While depleting CDK4 and 6 was sufficient to limit proliferation in specific resistance settings, RB loss rendered cells completely independent of these kinases. The main downstream target in this context was the activation status of CDK2, which was suppressed with CDK4/6 inhibition in an RB-dependent fashion. Protein levels of p27 were associated with plasticity/rigidity of the cell cycle and correlated with sensitivity to CDK4/6 inhibition. Exogenous overexpression and pharmacologic induction of p27 via inhibition of SKP2 and targeting the MEK/ERK pathway enhanced the cytostatic effect of CDK4/6 inhibitors. Mice bearing ER+ xenografts displayed a durable antitumor response to palbociclib; however, over the course of treatment, few cells retained RB phosphorylation, which was associated with limited p27 protein levels as determined by multispectral imaging. Similarly, combination treatment of palbociclib with a MEK inhibitor in pancreatic cancer PDX models upregulated p27 and further enhanced the in vivo tumor response to palbociclib. Collectively, these results suggest that the cell cycle plasticity, which enables tumor models to evade palbociclib-mediated activation of RB, could be targeted using a clinically applicable CDK2 inhibitor. SIGNIFICANCE: This work provides a mechanistic insight toward understanding the functional roles of multiple cell cycle regulators that drive plasticity and sensitivity to CDK4/6 inhibition. > >
웹 에디터 끝
첨부파일
파일추가
파일삭제
자동등록방지
숫자음성듣기
새로고침
자동등록방지 숫자를 순서대로 입력하세요.
작성완료
취소
전화걸기
문자상담
PL
MEMBERS