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Tumor Discovery CDK4/6 inhibitor resistance in breast cancer

Figure 1. Schematic diagram illustrating the mechanisms of action and resistance of CDK4/6 inhibitors in combination with endocrine therapy.
Abbreviations: CDK4/6: Cyclin-dependent kinase 4 and 6; MHC1: Major histocompatibility complex class 1; MDSCs: Myeloid-derived suppressor
cells; Treg: Regulatory T cell; TAM: Tamoxifen; T: Testosterone; AI: Aromatase inhibitors; E2: Estradiol; PD-L1: Programmed death-ligand 1; ERα:
Estrogen receptor alpha; E2F: E2F transcription factor; Rb: Retinoblastoma; AURKA: Aurora kinase A; RAS: Rat sarcoma; BRAF: B-Raf protooncogene;
MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; mTOR: Mammalian target of rapamycin.

biology occur during treatment. Understanding these regulation and activates alternative pathways that support
resistance mechanisms is crucial for devising effective tumor growth. 20,21 A detailed schematic representation of
strategies to overcome them and improve patient outcomes. these pathways is demonstrated in Figure 1.
3.1. Intrinsic resistance mechanisms 3.2. Acquired resistance mechanisms
Intrinsic resistance refers to the inherent ability of some Acquired resistance to CDK4/6 inhibitors typically
tumors to resist CDK4/6 inhibitors from the outset. One develops after an initial period of therapeutic sensitivity,
of the most significant mechanisms involves the loss or primarily due to genetic and epigenetic alterations within
mutation of the RB protein, a critical cell cycle regulator. the tumor. Common mutations in genes such as the RB
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Tumors lacking functional RB bypass CDK4/6 inhibition, protein, protein kinase B (AKT), rat sarcoma, aurora
allowing uninterrupted cell cycle progression. 12,19 kinase A (AURKA), and cyclin E have been identified
In addition, overexpression of CDK4 or CDK6 can as key drivers of resistance. These mutations activate
independently drive cell cycle progression by promoting alternative signaling pathways that bypass CDK4/6
RB phosphorylation, thereby enabling tumor cells to evade activity, thereby diminishing the efficacy of treatment. As
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the inhibitory effects of CDK4/6 inhibitors. 19,20 Similarly, illustrated in Figure 1, tumors can engage compensatory
the upregulation of cyclins, particularly cyclin D1, D2, pathways such as phosphoinositide 3-kinase (PI3K)/AKT
or D3, contributes to resistance by forming hyperactive or mitogen-activated protein kinase (MAPK) signaling,
complexes with CDK4/6 that are less susceptible to to sustain cell survival and proliferation despite CDK4/6
inhibition. In some tumors, especially ER-positive breast inhibition. This adaptive rewiring of signaling networks
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cancer, non-canonical activation of CDK2 facilitates undermines the long-term effectiveness of CDK4/6
S-phase entry despite CDK4/6 inhibition. This mechanism inhibitors. 12,22 In addition, changes in ER status, including
allows cancer cells to sustain proliferation even in the loss or downregulation, have been associated with
presence of inhibitors. 12,21 Furthermore, paradoxical reduced responsiveness to combined endocrine therapy
resistance can arise from the overexpression of p16INK4a and CDK4/6 inhibition. Epigenetic modifications
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proteins. Although p16INK4a typically inhibits CDK4/6 further contribute to acquired resistance by altering gene
activity, its overexpression disrupts normal cell cycle expression profiles, enabling tumors to adapt their growth

Volume 4 Issue 1 (2025) 29 doi: 10.36922/td.7107