Epigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor

Abstract

Hormone receptor-positive, HER2-negative advanced breast cancers exhibit high sensitivity to CDK4/6 inhibitors such as palbociclib. However, most patients inevitably develop resistance, thus identification of new actionable therapeutic targets to overcome the recurrent disease is an urgent need. Immunohistochemical studies of tissue microarray revealed increased activation of non-receptor tyrosine kinase, ACK1 (also known as TNK2) in most of the breast cancer subtypes, independent of their hormone receptor status. Chromatin immunoprecipitation studies demonstrated that the nuclear target of activated ACK1, pY88-H4 epigenetic marks, were deposited at cell cycle genes, CCNB1, CCNB2 and CDC20, which in turn initiated their efficient transcription. Pharmacological inhibition of ACK1 using its inhibitor, (R)-9b dampened CCNB1, CCNB2 and CDC20 expression, caused G2/M arrest, culminating in regression of palbociclib-resistant breast tumor growth. Further, (R)-9b suppressed expression of CXCR4 receptor, which resulted in significant impairment of metastasis of breast cancer cells to lung. Overall, our pre-clinical data identifies activated ACK1 as an oncogene that epigenetically controls the cell cycle genes governing the G2/M transition in breast cancer cells. ACK1 inhibitor, (R)-9b could be a novel therapeutic option for the breast cancer patients that have developed resistance to CDK4/6 inhibitors.

Small molecule agents for triple negative breast cancer: Current status and future prospects

“…ACK1 can promote the growth of BC by interacting with the estrogen receptor (ER) /histone demethylase KDM3A complex [285] . Excessive activation of ACK1 can promote the efficient transcription of cell cycle genes such as CCNB1 and CCNB2, making BC cells resistant to CDK4/6 inhibitors [286] . ACK1 inhibitor ( R )−9bMS can not only inhibit the proliferation of TNBC [287] , but also block the cell cycle and make the growth of drug-resistant HR+/HER2- BC fade [286] .…”

“…Excessive activation of ACK1 can promote the efficient transcription of cell cycle genes such as CCNB1 and CCNB2, making BC cells resistant to CDK4/6 inhibitors [286] . ACK1 inhibitor ( R )−9bMS can not only inhibit the proliferation of TNBC [287] , but also block the cell cycle and make the growth of drug-resistant HR+/HER2- BC fade [286] . Previous studies have shown that dasatinib monotherapy is ineffective in the treatment of TNBC, the ORR was 4.7 %, the DCR was 9.3 % and the mPFS was only 8.3 weeks after intervention with either 100 mg or 70 mg of dasatinib twice daily [288] .…”

Prostate cancer immunotherapy: Improving clinical outcomes with a multi-pronged approach

“…ACK1 protein encoded by the TNK2 gene is a ubiquitously expressed non-receptor tyrosine kinase that is overexpressed in multiple tumors, including prostate and breast, where its expression is correlated with increased invasiveness and poor prognosis. 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 ACK1 is activated by multiple growth factors, including PDGF, FGF, EGF, heregulin, GAS6, and insulin, and its knockdown increases apoptosis. 121 , 125 ACK1 plays a crucial role in increasing WDR5/MLL2 complex-mediated AR transcriptional activation by phosphorylating histone H4 at tyrosine 88 (pY88-H4) in the AR enhancer region.…”