Effects of CDK4/6 Inhibition in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Cells with Acquired Resistance to Paclitaxel

Abstract

Among patients with hormone receptor (HR)-positive breast cancer, those with residual disease after neoadjuvant chemotherapy have a higher risk of relapse and poorer survival than those with a complete response. Previous studies have revealed a correlation between activation of cell cycle-regulating pathways in HR-positive breast cancer, particularly cyclin-dependent kinase (CDK) 4 and 6/cyclin D1 signaling, and resistance to standard therapies. Although CDK4/6 inhibition by palbociclib in combination with endocrine therapy has shown potent antiproliferative effects in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the potential role of palbociclib in re-sensitizing chemotherapy-resistant HR-positive breast cancer is not well defined. We hypothesized that CDK4/6 inhibition by palbociclib re-sensitizes HR-positive/HER2-negative residual breast cancer to taxane-based adjuvant therapy. Using cell counting, flow cytometry, and western blotting, we evaluated the efficacy of palbociclib alone and in concurrent or sequential combination with paclitaxel in parental and paclitaxel-resistant T47D HR-positive/HER2-negative breast cancer cells. The CDK4/6 pathway was constitutively active in both parental and paclitaxel-resistant T47D cells; thus, both cell types were highly sensitive to the inhibitory effects of single-agent palbociclib on cell growth and cell cycle progression. However, palbociclib did not re-sensitize resistant cells to paclitaxel-induced G2/M arrest and cell death in any of the combinations tested. Our results suggest that CDK4/6 inhibition by palbociclib does not re-sensitize HR-positive/HER2-negative residual breast cancer to chemotherapy. Nevertheless, the fact that CDK4/6 activation remained intact in paclitaxel-resistant cells indicates that patients who have HR-positive/HER2-negative residual disease after taxane-based neoadjuvant chemotherapy may still benefit from palbociclib in combination with other regimens, such as endocrine therapies, for adjuvant therapy.

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

“…2012]. Palbociclib did not resensitize paclitaxel-resistant cells to paclitaxel-induced apoptosis [Trapé et al . 2016].…”

“…Palbociclib did not resensitize paclitaxel-resistant cells to paclitaxel-induced apoptosis [Trapé et al 2016]. Nonetheless, a short exposure to palbociclib to synchronize cells prior to paclitaxel resulted in increased cytotoxicity [Dean et al 2012a].…”

MiR-138-5p targeting LIMK1 suppresses breast cancer cell proliferation and motility

“…Cyclin D1 is an important regulator for the G1/S transition, through activating CDK4/6, which phosphorylate and inactivate pRb to release the transcription factor E2F to initiate a series of genes that required for cell cycle progression through the G1/S transition. 35 CDK2/Cyclin E1 compound also played a major role in inducing cell cycle from G1 phase to S phase. 36 Aer transfected with miR-138-5p mimics into MDA-MB-231 and HCC1937 cells, CDK4, 6/Cyclin D1 and CDK2/Cyclin E1 compounds expression all reduced in both two cellines.…”

Recent advances of highly selective CDK4/6 inhibitors in breast cancer

“…Besides, this compound can also sensitize cancer cells to other regimes when in combination, such as chemotherapy [ 50 ] and ionizing radiation [ 51 ]. The potent anti-tumor effects of palbociclib have been observed in several tumor types, including T cell acute lymphoblastic leukemia (T-ALL) [ 45 ], hepatocellular carcinoma [ 39 ], neuroblastoma [ 40 ], renal cell carcinoma [ 52 ], myeloma [ 53 ], mantle cell lymphoma [ 54 ], pancreatic ductal adenocarcinoma [ 49 ], esophageal adenocarcinoma [ 55 ], medulloblastoma [ 51 ], melanoma [ 56 ], non-small cell lung carcinoma [ 57 ], and particularly in breast cancer [ 50 , 58 , 59 ].…”