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Tumor Discovery CDK4/6 inhibitor resistance in breast cancer

References 5,16,50,51 5,16,46,50,51 5,16,50-52 18,53-55 and survival strategies in response to ongoing therapy.
These modifications may include DNA methylation,
histone acetylation, or chromatin remodeling, which
21,22
collectively promote tumor plasticity and resistance.
Main Side effects Neutropenia Neutropenia, QTc prolongation Diarrhea, fatigue Neutropenia, leukopenia 3.3. Immune-mediated resistance mechanisms

Recent research has identified immune-mediated
mechanisms as a significant contributor to acquired
resistance against CDK4/6 inhibitors. These inhibitors
have been shown to reprogram transcriptional activity

Dosing schedule 21 days on/ 7 days off 21 days on/ 7 days off Continuous dosing 21 days on/ 7 days off in both tumor and immune cells, enhancing tumor
immunogenicity and fostering an immune-enriched tumor
microenvironment. However, tumors can counteract
23
these effects by upregulating immune checkpoint
proteins, such as programmed cell death-ligand 1, and
Cellular effect Cytostasis only Cytostasis only Both cytostasis and cytotoxicity Induces G1 arrest and cellular senescence disrupting antigen presentation mediated by the major
histocompatibility complex (MHC). These adaptations
enable immune evasion and establish immunosuppressive
conditions within the tumor microenvironment.
24,25
This resistance is further exacerbated by a decrease in
regulatory T cells (Tregs) and myeloid-derived suppressor
Additional targets Highly specific for CDK4/6 Highly specific for CDK4/6 Also inhibits CDK1, CDK2, CDK5, CDK9, and other kinases Specific for CDK4/6 cells (MDSCs), which play a pivotal role in maintaining
anti-tumor immunity (Figure 1). Paradoxically, while
26
CDK4/6 inhibitors reduce Tregs and MDSCs, the resulting
immune dysregulation can promote tumor adaptation.
Tumors may also undergo phenotypic changes as a form
of adaptive resistance, allowing them to evade immune
surveillance even after an initial response to CDK4/6

4. Novel biomarkers for predicting
Binding affinity Similar affinity for CDK4/cyclin D3 and CDK6/cyclin D1 5-fold greater affinity for CDK4/ cyclin D3 9-fold greater affinity for CDK4/ cyclin D3; 14 times more potent against CDK4 than CDK6 Shows selectivity toward CDK4 and CDK6 Abbreviations: ATP: Adenosine triphosphate; CDK: Cyclin-dependent kinase; CDK4/6: Cyclin-dependent kinase 4 and 6; QTc: Corrected QT interval. inhibitor therapy. 23,25
resistance
Table 1. Comparison of the mechanisms of four CDK4/6 inhibitors
Circulating tumor DNA (ctDNA) analysis has emerged as a
highly promising method for tracking treatment responses
and identifying resistance mechanisms to CDK4/6
inhibitors. Sequential ctDNA assessments demonstrate
IC50 values Similar potency for CDK4 and CDK6 CDK4: 10 nM CDK6: 39 nM CDK4: 2 nM, CDK6: 10 nM CDK4: 12.4 nM, CDK6: 9.9 nM high sensitivity (75%) and specificity (92%) in detecting
disease progression, often identifying an increase in tumor
DNA approximately three months before radiological
evidence of progression. This non-invasive approach is
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Mechanism type ATP-competitive ATP-competitive ATP-competitive ATP-competitive particularly valuable for monitoring treatment responses
in challenging scenarios, such as bone metastases or small-
sized target lesions, where traditional imaging modalities
may have limitations.
27,28
Compared to conventional serum tumor markers,
Primary target CDK4/6 CDK4/6 CDK4/6 CDK4/6 such as carcinoembryonic antigen or cancer antigen 15-3,
ctDNA analysis offers superior sensitivity for monitoring
tumor response to CDK4/6 inhibitors. Moreover,
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CDK4/6 inhibitor Palbociclib Ribociclib Abemaciclib Dalpiciclib ctDNA has proven effective in detecting acquired genetic
alterations associated with resistance to these inhibitors.
For example, loss of function in the RB gene is strongly

Volume 4 Issue 1 (2025) 30 doi: 10.36922/td.7107