CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review

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.

Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction

“…G1/S cyclins, such as Cyclin D and E, are one of the master regulators in cancer. Accumulation of the cyclin D-cyclin-dependent protein kinase (CDK)4/6 complex partially phosphorylates the retinoblastoma tumor suppressor protein (Rb), whose inhibition is important for cell cycle progression [ 32 ]. The cyclin E-CDK2 complex phosphorylates the cyclin D inhibitor p27Kip1, marks it for degradation, initiates the assembly of the pre-replication complex and promotes the expression of cyclin A, which determines the initiation of DNA replication [ 33 ].…”

The role of CXCL1 in crosstalk between endocrine resistant breast cancer and fibroblast

“…Recently, many studies have sought out to the interaction between CDK4/6 inhibitors and other antitumor agents including SERM, SERD, chemotherapy agents, immune checkpoint inhibitors, autophagy inhibitor, Hippo Pathway Inhibitor, and AP-1 Inhibitor. In addition, RTK inhibitors, mTOR inhibitors, and Ras inhibitors were utilized to inhibit the CDK4/6 inhibitor resistant tumors (37). Given the combination therapies with CDK4/6 inhibitors, this led us to hypothesize that reparixin could be a strong potential therapeutic drug partner.…”

Aromatase inhibition plus/minus Src inhibitor saracatinib (AZD0530) in advanced breast cancer therapy (ARISTACAT): a randomised phase II study

“…In the saracatinib/AI group, OS was 24.1 months [95% CI 17.0-31.1], compared with 22.9 months [95% CI 19.5-26.3] in the placebo/AI group (one sided p = 0.88), indicating no significant difference in OS between treatments arms. When conducting a planned subgroup analysis, OS data were similar in the "AI-sensitive/naïve" (saracatinib/AI 24 The total number of deaths in the saracatinib/AI group was 39 (55%). Thirty-four (87%) of those were related to breast cancer and 5 (13%) were unrelated (infection/sepsis [n = 2], pulmonary emboli [n = 2], unknown [n = 1]).…”