Page 41 - TD-4-1

Tumor Discovery CDK4/6 inhibitor resistance in breast cancer

mutation status, and individual patient factors. Ongoing activation. 12,13 Furthermore, personalized combination
clinical trials are evaluating novel agents and combinations therapies targeting multiple pathways are being developed
to further improve outcomes for patients with CDK4/6 based on individual tumor molecular profiles. For instance,
inhibitor-resistant breast cancer. 45,46 combining CDK4/6 inhibitors with PI3K/AKT/mTOR
pathway inhibitors has shown promise in overcoming
7. Future directions in research and clinical resistance by addressing compensatory signaling pathways
practice frequently activated in resistant tumors.
Ongoing clinical trials are focused on developing novel 8. Conclusion
strategies to overcome resistance to CDK4/6 inhibitors.
These include combination therapies pairing CDK4/6 CDK4/6 inhibitors have revolutionized the treatment
inhibitors with immune checkpoint inhibitors across landscape for HR-positive/HER2-negative breast cancer,
various cancer types, leveraging the immunomodulatory significantly improving PFS and OS. However, resistance
effects of CDK4/6 inhibitors to enhance anti-tumor to these therapies remains a critical clinical challenge.
immunity. As shown in Figure 1, CDK4/6 inhibitors Ongoing research into resistance mechanisms, the
23
increase MHC class I expression, reduce Tregs, and development of predictive biomarkers to guide treatment,
promote cytotoxic T lymphocyte activation, creating a and novel therapeutic strategies offer hope for enhancing
tumor microenvironment conducive to immunotherapy. treatment efficacy and extending benefits to a broader
In addition, researchers are exploring innovative range of patients.
dosing regimens, such as intermittent dosing or lead-in Acknowledgments
23
periods, to optimize efficacy while minimizing toxicity.
Expanding the scope of CDK4/6 inhibitors beyond None.
advanced HR-positive/HER2-negative breast cancer is
another area of interest. Trials are assessing their efficacy Funding
in diverse breast cancer subtypes and clinical scenarios, None.
including early-stage disease and tumors with unique
molecular profiles. 4 Conflict of interest
In terms of resistance detection, emerging The authors declare they have no competing interests.
technologies like ctDNA analysis are being utilized for
their non-invasive nature in detecting genetic alterations Author contributions
associated with resistance. ctDNA has proven effective Conceptualization: Jundong Wu, Chunfa Chen
in identifying RB mutations, MYC amplifications, and Visualization: Bingfeng Chen, Rendong Zhang, Chunfa
cyclin E overexpression – key markers of resistance to Chen
CDK4/6 inhibitors – often months before radiological Writing–original draft: Yuling Zhang, Chunfa Chen
progression. 27,30 This ability of early detection allows for Writing–review & editing: Jundong Wu, Chunfa Chen
more informed treatment decisions and personalized
therapeutic strategies. Genomic profiling is also being Ethics approval and consent to participate
49
employed to uncover novel genetic alterations linked to
resistance, including loss-of-function mutations in FAT Not applicable.
atypical cadherin 1, which may contribute to bypassing Consent for publication
CDK4/6 inhibition. 49
Not applicable.
Personalized medicine approaches are at the forefront
of current research, with biomarker-driven treatment Availability of data
selection playing a pivotal role. Reliable biomarkers such
as RB status or cyclin E protein expression levels are being Not applicable.
investigated to predict response to CDK4/6 inhibitors. 12,49 References
Adaptive treatment strategies are also under investigation,
which involve modifying therapy based on early molecular 1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics
or clinical indicators of response or resistance. For example, 2022: GLOBOCAN estimates of incidence and mortality
switching to alternative therapies or adding targeted worldwide for 36 cancers in 185 countries. CA Cancer J Clin.
agents like PI3K/AKT/mTOR inhibitors may counter 2024;74(3):229-263.
specific resistance mechanisms in tumors with pathway doi: 10.3322/caac.21834

Volume 4 Issue 1 (2025) 33 doi: 10.36922/td.7107