Resistance to targeted therapies in HER2+ breast cancer is mediated by cyclin D1 and CDK4.
Major finding: Resistance to targeted therapies in HER2+ breast cancer is mediated by cyclin D1 and CDK4.
Mechanism: CDK4/6 inhibition reduces TSC2 phosphorylation, reducing mTORC1 activity and cell proliferation.
Impact: In HER2+ breast cancer CDK4/6 inhibitors may resensitize resistant tumors to EGFR/HER2 inhibition.
Approximately 15% of breast cancers overexpress the human epidermal growth factor receptor 2 (HER2), which can be effectively targeted with inhibitors of HER2 or EGFR. However, drug resistance often develops in patients, leading to disease progression and relapse at local or distant sites. In order to better understand the mechanisms of recurrence and resistance in HER2+ breast cancer, Goel and colleagues generated a transgenic mouse model of the disease driven by the doxycycline-inducible expression of human HER2 in the mammary glands. Induction of HER2 resulted in HER2+ breast tumors that recapitulated the human disease. Although withdrawal of doxycycline to simulate HER2 blockade in tumor-bearing mice resulted in tumor regression, approximately two thirds of the mice eventually developed HER2-independent recurrent mammary tumors. RNA sequencing of primary and recurrent tumors indicated that recurrent tumors had increased expression of genes that promote cell-cycle progression including CCND1 (encoding cyclin D1) and CDK4. In addition, the tumor cells that survived the initial HER2 withdrawal expressed high levels of cyclin D1. In cell lines, CCND1 knockdown increased the sensitivity of HER2-resistant cells to HER2 inhibition, suggesting its importance in mediating resistance to HER2 inhibitors. Moreover, combined inhibition of CDK4/6, with abemaciclib, and HER2 resulted in a synergistic reduction in cell proliferation in HER2 inhibitor–sensitive cells, and restored sensitivity to HER2 inhibition in resistant cells. Abemaciclib treatment after withdrawal of HER2 in the recurrent tumor model delayed tumor recurrence. Mechanistically, abemaciclib reduced phosphorylation and activation of TSC2, which is upstream of mTORC1 and led to reduced mTORC1 activity. Combined inhibition of HER2 and CDK4/6 further suppressed mTORC activity, abolishing phosphorylation and activation of p70S6K, S6RP, and pRb, reducing proliferation, and enhancing cell-cycle arrest. Together, these results elucidate a mechanism by which HER2+ breast tumors develop resistance to targeted therapies, and indicate that CDK4/6 inhibitors in combination with HER2 targeted therapy may delay tumor recurrence.
- ©2016 American Association for Cancer Research.