CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions

Abstract

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and the improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor-positive metastatic breast cancer.

Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer

“…Although the use of CDK4/6 inhibitors improved the outcomes of BCs resistant to ET, many different mechanisms of resistance to CDK4/6is have been reported [ 42 , 43 ]. These include (a) alterations in genes controlling cell cycle regulation, (b) the activation of alternative pathways, and (c) changes in transcriptional and epigenetic modifiers.…”

“…Additionally, the over-expression of the CCNE1 gene, encoding another cyclin, namely cyclin E1 (the crucial cofactor for CDK2 necessary for RB hyper-phosphorylation), was linked to a limited response to palbociclib in the PALOMA-3 study [ 45 ]. Activating mutations in critical domains of CDK4/6 themselves (i.e., the ATP-binding pocket) have also been described to favor resistance [ 43 ]. Given that the retinoblastoma protein (RB) is the main phosphorylation target of CDK4/6 to stimulate cell cycle progression, inactivating mutations or the loss of the RB1 gene was found in different BC patients with reduced sensitivity to CDK4/6 inhibitors [ 46 , 47 ].…”

Synthesis and Preclinical Evaluation of Novel 68Ga-DOTA-RBB as Potential PET Radiotracer for Imaging CDK4/6 in Tumors

“…19 Despite the increasing development and clinical application of CDK4/6 inhibitors for the treatment of ER+/HER2-breast cancer, resistance often emerges, which ultimately leads to poorer prognoses for patients. 20,21 Given this, it is essential to create an in vivo imaging method for CDK4/6 to enhance the detection rate of lesions and improve patient prognosis. Additionally, in clinical settings, precise diagnosis of tumors often relies on pathological examinations.…”

“…Breast cancer, being among the most prevalent malignancies worldwide, poses a significant threat to the well-being and lives of women. , Moreover, the HR-positive/HER2-negative subtype of breast cancer accounts for 65% to 70% of breast cancer occurrences . Despite the increasing development and clinical application of CDK4/6 inhibitors for the treatment of ER+/HER2- breast cancer, resistance often emerges, which ultimately leads to poorer prognoses for patients. , Given this, it is essential to create an in vivo imaging method for CDK4/6 to enhance the detection rate of lesions and improve patient prognosis.…”

Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches

“…In recent years, several enzymes emerged as potential biomarkers for the diagnosis or prognosis of several malignancies [ 9 , 10 , 11 , 12 , 13 , 14 ]. Moreover, the possibility of designing specific inhibitors has also opened the possibility of utilizing these biomarkers as therapeutic targets [ 15 , 16 , 17 , 18 ]. The need to discover novel enzymatic pathways dysregulated in cancer, as well as identifying novel potential therapeutic targets for cancer management, was highlighted by several papers published in this Special Issue.…”