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Tumor Discovery CDK4/6 inhibitor resistance in breast cancer

1. Introduction outcomes, developing novel therapies, and optimizing
treatment sequencing. 5,12-14 This review aims to provide a
Breast cancer is the most prevalent malignant tumor in comprehensive summary of current resistance mechanisms
women, constituting approximately 11.6% of all cancer to CDK4/6 inhibitors and explore potential approaches to
diagnoses worldwide. In 2022, nearly 2.5 million new breast overcome such resistance.
cancer cases were recorded globally, representing roughly
1
a quarter of all cancer cases. It is categorized into three 2. The operational mechanism and clinical
subtypes depending on the presence of estrogen receptor application of CDK4/6 inhibitors
(ER), progesterone receptor, and human epidermal
growth factor receptor 2 (HER2): hormone receptor (HR)- As illustrated in Figure 1, CDK4/6 kinases are pivotal
positive, HER2-positive, and triple-negative. Among these, in governing cell cycle progression, especially during
HR-positive breast cancer accounts for approximately 60% the transition from the G1 phase to the S phase. They
to 70% of all cases. Although HR-positive breast cancer is form complexes with cyclin D1 proteins, which then
generally associated with a better prognosis compared to phosphorylate the RB protein, which is a key tumor
15
other subtypes, patients with this subtype still experience suppressor. Phosphorylation of RB disrupts its interaction
two distinct peaks of recurrence – one occurring within with E2F transcription factors, thereby releasing E2F
the first 1 – 3 years and another even after 10 years – to activate the transcription of genes essential for DNA
15
underscoring the urgent need for novel therapeutic replication and cell cycle progression. In HR-positive/
strategies to improve long-term patient outcomes. 2,3 HER2-negative breast cancer, CDK4/6 inhibitors are used
in conjunction with anti-estrogen therapies, including
Building on the foundation of endocrine therapy, aromatase inhibitors (AIs), fulvestrant, and tamoxifen, to
cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors achieve a synergistic effect. This combination has become
16
have emerged as powerful targeted therapies, particularly the standard of care for advanced HR-positive/HER2-
for HR-positive breast cancer. CDK4 and CDK6 are negative breast cancer. Currently, four selective CDK4/6
17
crucial regulators of the G1-to-S phase transition in the inhibitors have been approved, including palbociclib,
cell cycle, a process essential for cellular proliferation. ribociclib, dalpiciclib, and abemaciclib. These agents
4
5,18
These kinases form complexes with D-type cyclins, specifically target CDK4/6 kinase and exhibit comparable
particularly cyclin D1, which phosphorylate and inactivate inhibitory effects on both kinases. Palbociclib, dalpiciclib,
the retinoblastoma (RB) tumor suppressor protein. This and ribociclib share structural similarities and display
phosphorylation releases E2F transcription factors, similar kinase inhibitory activities. These drugs are
enabling the transcription of genes required for DNA typically administered on a three-week-on, one-week-
synthesis and cell cycle progression. By blocking CDK4/6 off schedule to mitigate myelosuppression, their primary
5
activity, these drugs prevent the phosphorylation of RB, dose-limiting toxicity. In contrast, abemaciclib exhibits a
5,18
thereby inhibiting cell cycle progression and tumor growth. distinct inhibitory profile, with higher selectivity for CDK4
The combination of CDK4/6 inhibitors with endocrine compared to CDK6, consistent with its reported high
therapy has significantly benefited both early-stage and potency against CDK4. In addition, abemaciclib inhibits
5
advanced HR-positive/HER2-negative breast cancer, multiple other kinases, including CDK1, CDK2, CDK5,
transforming the treatment paradigm. Clinical trials such CDK9, and albeit at lower potencies. The predominant
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as NATALEE and MONARCH E have expanded treatment toxicities of abemaciclib are diarrhea and fatigue. A
5
options for patients with early HR-positive/HER2-negative comparative summary of the mechanisms and side effect
breast cancer, demonstrating the potential of CDK4/6 profiles of these four CDK4/6 inhibitors is shown in
inhibitors to reduce recurrence risk and improve overall Table 1.
survival (OS). Furthermore, advanced clinical trials,
6,7
10
such as PALOMA-2, MONALEESA-7 and -3, and 3. Mechanisms of resistance to CDK4/6
8
9
MONARCH-3 have shown that this combination therapy inhibitors
11
significantly improves progression-free survival (PFS) Resistance to CDK4/6 inhibitors can be broadly categorized
for patients with metastatic HR-positive/HER2-negative into two types: intrinsic and acquired, each driven by
breast cancer. distinct mechanisms that contribute to treatment failure,
However, resistance to CDK4/6 inhibitor therapy particularly in HR-positive/HER2-negative breast cancer.
remains a significant clinical challenge, resulting in disease Intrinsic resistance arises from pre-existing genetic or
progression in some early-stage patients and nearly all molecular alterations that render tumor cells inherently
advanced-stage patients. Understanding the underlying unresponsive to CDK4/6 inhibition. In contrast, acquired
mechanisms of resistance is crucial for improving patient resistance develops over time as adaptive changes in tumor

Volume 4 Issue 1 (2025) 28 doi: 10.36922/td.7107