CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review
Gian Luca Rampioni Vinciguerra1,2, Maura Sonego1, Ilenia Segatto1
1Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), National Cancer Institute, Aviano, Italy.
Abstract:
The cyclin D-CDK4/6 complexes play a pivotal role in controlling the cell cycle. Deregulation in cyclin D-CDK4/6 pathway has been described in many types of cancer and it invariably leads to uncontrolled cell proliferation. Many efforts have been made to develop a target therapy able to inhibit CDK4/6 activity. To date, three selective CDK4/6 small inhibitors have been introduced in the clinic for the treatment of hormone positive advanced breast cancer patients, following the impressive results obtained in phase III clinical trials. However, since their approval, clinical evidences have demonstrated that about 30% of breast cancer is intrinsically resistant to CDK4/6 inhibitors and that prolonged treatment eventually leads to acquired resistance in many patients. So, on one hand, clinical and preclinical studies fully support to go beyond breast cancer and expand the use of CDK4/6 inhibitors in other tumor types; on the other hand, the question of primary and secondary resistance has to be taken into account, since it is now very clear that neoplastic cells rapidly develop adaptive strategies under treatment, eventually resulting in disease progression. Resistance mechanisms so far discovered involve both cell-cycle and non-cell-cycle related escape strategies. Full understanding is yet to be achieved but many different pathways that, if targeted, may lead to reversion of the resistant phenotype, have been already elucidated. Here, we aim to summarize the knowledge in this field, focusing on predictive biomarkers, to recognize intrinsically resistant tumors, and therapeutic strategies, to overcome acquired resistance.
Insights
CDK4/6 inhibitors show promise for various cancers but face resistance. Research focuses on biomarkers and strategies to overcome both intrinsic and acquired resistance for improved therapeutic outcomes.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Cyclin D-CDK4/6 complexes are crucial for cell cycle regulation.
- Deregulation of this pathway drives cancer cell proliferation.
- Selective CDK4/6 inhibitors are approved for hormone-positive advanced breast cancer.
Purpose of the Study:
- To review predictive biomarkers for intrinsic resistance to CDK4/6 inhibitors.
- To summarize therapeutic strategies for overcoming acquired resistance.
- To explore expanding CDK4/6 inhibitor use beyond breast cancer.
Main Methods:
- Review of clinical and preclinical studies on CDK4/6 inhibitors.
- Analysis of identified resistance mechanisms (cell-cycle and non-cell-cycle related).
- Focus on elucidating pathways for therapeutic targeting.
Main Results:
- Approximately 30% of breast cancers exhibit intrinsic resistance to CDK4/6 inhibitors.
- Acquired resistance develops in many patients with prolonged treatment.
- Various adaptive strategies contribute to resistance, necessitating further research.
Conclusions:
- Understanding resistance mechanisms is critical for effective CDK4/6 inhibitor therapy.
- Targeting specific pathways may reverse resistant phenotypes.
- Further research is needed to identify biomarkers and develop strategies to overcome resistance.
