p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases

Jing Ni; Sheheryar Kabraji; Shaozhen Xie; Yanzhi Wang; Peichen Pan; Xiaofang He; Zongming Liu; Jose Palbo Leone; Henry W Long; Myles A Brown; Eric P Winer; Deborah A R Dillon; Nancy U Lin; Jean J Zhao

doi:10.1038/s41467-022-29081-2

p16^INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases

Nat Commun. 2022 Mar 18;13(1):1473. doi: 10.1038/s41467-022-29081-2.

Authors

Jing Ni^#^{1

2}, Sheheryar Kabraji^#^{1

3

4}, Shaozhen Xie^{1

2}, Yanzhi Wang¹, Peichen Pan^{1

2

5}, Xiaofang He^{1

6}, Zongming Liu^{1

7

8}, Jose Palbo Leone³, Henry W Long⁹, Myles A Brown^{3

9}, Eric P Winer³, Deborah A R Dillon¹⁰, Nancy U Lin³, Jean J Zhao^{11

12

13}

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
⁴ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
⁵ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, P. R. China.
⁶ Department of Radiation Oncology, the first affiliated hospital of Sun Yat-Sen University, Guangzhou, 510080, P. R. China.
⁷ Key Laboratory of Bionic Engineering (Ministry of Education), College of Biological and Agricultural Engineering, Jilin University, Changchun, Jilin, 130022, P. R. China.
⁸ Department of Anesthesiology, Jilin Cancer Hospital, Changchun, Jilin, 130000, P. R. China.
⁹ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹⁰ Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
¹¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. jean_zhao@dfci.harvard.edu.
¹² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA. jean_zhao@dfci.harvard.edu.
¹³ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA. jean_zhao@dfci.harvard.edu.

^# Contributed equally.

Abstract

Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16^INK4A is deficient in the majority of HER2+ BCBMs. p16^INK4A-deficiency as measured by protein immunohistochemistry predicted response to combined tucatinib and abemaciclib in orthotopic patient-derived xenografts (PDXs) of HER2 + BCBMs. Our findings establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2 + BCBM.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / therapeutic use
Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Brain Neoplasms* / pathology
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Female
Humans
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism

Substances

Antineoplastic Agents
Cyclin-Dependent Kinase Inhibitor p16
Receptor, ErbB-2
CDK4 protein, human
Cyclin-Dependent Kinase 4

Abstract

Publication types

MeSH terms

Substances

Grants and funding