INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors Journal Article


Authors: Li, Q.; Jiang, B.; Guo, J.; Shao, H.; Del Priore, I. S.; Chang, Q.; Kudo, R.; Li, Z.; Razavi, P.; Liu, B.; Boghossian, A. S.; Rees, M. G.; Ronan, M. M.; Roth, J. A.; Donovan, K. A.; Palafox, M.; Reis-Filho, J. S.; de Stanchina, E.; Fischer, E. S.; Rosen, N.; Serra, V.; Koff, A.; Chodera, J. D.; Gray, N. S.; Chandarlapaty, S.
Article Title: INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors
Abstract: Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identified several genetic alterations (e.g., FAT1, PTEN, or ARID1A loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18INK4C). In vitro binding and kinase assays together with physical modeling reveal that the p18INK4C–cyclin D–CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects in vivo, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance. © 2021 The Authors; Published by the American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 12
Issue: 2
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2022-02-01
Start Page: 356
End Page: 371
Language: English
DOI: 10.1158/2159-8290.Cd-20-1726
PUBMED: 34544752
PROVIDER: scopus
PMCID: PMC8831444
DOI/URL:
Notes: Article -- Export Date: 1 March 2022 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    418 Rosen
  2. Andrew C Koff
    105 Koff
  3. Qing Chang
    34 Chang
  4. Zhiqiang Li
    10 Li
  5. John Damon Chodera
    107 Chodera
  6. Pedram Razavi
    142 Razavi
  7. Bo Liu
    22 Liu
  8. Qing Li
    10 LI
  9. Hong Shao
    9 Shao
  10. Jiaye Guo
    2 Guo
  11. Rei Kudo
    1 Kudo