Immunomodulatory effects of CDK4/6 inhibitors

Zhang, Shumeng; Xu, Qiaomai; Sun, Wei; Zhou, Jianya; Zhang, Jianying

doi:10.1016/j.bbcan.2023.188912

Cited by 10 publications

(3 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, long-term in vitro cell-based assays may ultimately be useful for identifying better predictive biomarkers. Finally, the in vivo response to CDK4/6 inhibitors will also be affected by extrinsic effects on the tumour microenvironment and/or the immune system, which will not be captured using in vitro cell-based assays 50 . Nevertheless, it is likely that the induction of senescence, which leads to a senescence-associate secretory phenotype (SASP), will help to engage the immune system to promote tumour clearance 51 .…”

Section: Discussionmentioning

confidence: 99%

The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays

Foy,

Lew,

Saurin

2024

npj Breast Cancer

View full text Add to dashboard Cite

CDK4/6 inhibitors are effective at treating advanced HR+ /HER2- breast cancer, however biomarkers that can predict response are urgently needed. We demonstrate here that previous large-scale screens designed to identify which tumour types or genotypes are most sensitive to CDK4/6 inhibitors have misrepresented the responsive cell lines because of a reliance on metabolic proliferation assays. CDK4/6-inhibited cells arrest in G1 but continue to grow in size, thereby producing more mitochondria. We show that this growth obscures the arrest using ATP-based proliferation assays but not if DNA-based assays are used instead. Furthermore, lymphoma lines, previously identified as the most sensitive, simply appear to respond the best using ATP-based assays because they fail to overgrow during the G1 arrest. Similarly, the CDK4/6 inhibitor abemaciclib appears to inhibit proliferation better than palbociclib because it also restricts cellular overgrowth through off-target effects. DepMap analysis of screening data using reliable assay types, demonstrates that palbociclib-sensitive cell types are also sensitive to Cyclin D1, CDK4 and CDK6 knockout/knockdown, whereas the palbociclib-resistant lines are sensitive to Cyclin E1, CDK2 and SKP2 knockout/knockdown. Potential biomarkers of palbociclib-sensitive cells are increased expression of CCND1 and RB1, and reduced expression of CCNE1 and CDKN2A. Probing DepMap with similar data from metabolic assays fails to reveal these associations. Together, this demonstrates why CDK4/6 inhibitors, and any other anti-cancer drugs that arrest the cell cycle but permit continued cell growth, must now be re-screened against a wide-range of cell types using an appropriate proliferation assay. This would help to better inform clinical trials and to identify much needed biomarkers of response.

show abstract

Section: Discussionmentioning

confidence: 99%

The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays

Foy,

Lew,

Saurin

2024

npj Breast Cancer

View full text Add to dashboard Cite

show abstract

“…CXCL10 and C‐C motif chemokine ligand 5 (CCL5), in tumor cells. [ 23 ] Furthermore, treating tumor cells with CDK4/6i facilitates their recognition by the immune system via enhancing expression of major histocompatibility complex class I (MHC‐I). [ 24 , 25 ]…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporally Controlled T‐Cell Combination Therapy for Solid Tumor

Hao,

Zhou,

Chen

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Due to multidimensional complexity of solid tumor, development of rational T‐cell combinations and corresponding formulations is still challenging. Herein, a triple combination of T cells are developed with Indoleamine 2,3‐dioxygenase inhibitors (IDOi) and Cyclin‐dependent kinase 4/6 inhibitors (CDK4/6i). To maximize synergism, a spatiotemporally controlled T‐cell engineering technology to formulate triple drugs into one cell therapeutic, is established. Specifically, a sequentially responsive core‐shell nanoparticle (SRN) encapsulating IDOi and CDK4/6i is anchored onto T cells. The yielded SRN‐T cells migrated into solid tumor, and achieved a 1st release of IDOi in acidic tumor microenvironment (TME). Released IDOi restored tryptophan supply in TME, which activated effector T cells and inhibited Tregs. Meanwhile, 1st released core is internalized by tumor cells and degraded by glutathione (GSH), to realize a 2nd release of CDK4/6i, which induced up‐regulated expression of C‐X‐C motif chemokine ligand 10 (CXCL10) and C‐C motif chemokine ligand 5 (CCL5), and thus significantly increased tumor infiltration of T cells. Together, with an enhanced recruitment and activation, T cells significantly suppressed tumor growth, and prolonged survival of tumor‐bearing mice. This study demonstrated rationality and superiority of a tri‐drug combination mediated by spatiotemporally controlled cell‐engineering technology, which provides a new treatment regimen for solid tumor.

show abstract

“…They can effectively inhibit tumor cell proliferation, overcome or delay the emergence of endocrine resistance, and strive for longer patient survival time. [ 7 , 8 ] To date, a total of 4 CDK4/6 inhibitors have been approved for marketing in China for the treatment of HR+/HER2− locally advanced or metastatic breast cancer, namely palbociclib, ribociclib, abemaciclib, and dalpiciclib. Although these 4 CDK4/6 inhibitors have similar mechanisms of action, they still differ in efficacy, safety, price, and accessibility.…”

Section: Introductionmentioning

confidence: 99%

CDK4/6 inhibitors for hormone receptor-positive/human epidermal growth factor receptor 2 negative advanced breast cancer: A rapid health technology assessment

Gu,

Chen,

Xie

et al. 2023

Medicine

View full text Add to dashboard Cite

Object: Based on the best available evidence, rapid health technology was used to assess 4 CDK4/6 inhibitors approved for marketing in China. This assessment aims to provide a reference basis for the selection of drugs by medical institutions in China and to promote the rational use of drugs in the clinic. Methods: Depending on the Rapid Guidelines for Drug Evaluation and Selection in Chinese Medical Institutions (the Second Edition), a percentage quantitative scoring approach was used to objectively score the pharmacological properties, efficacy, safety, economy, and other attributes of CDK4/6 inhibitors. Results: The composite score rankings were, in descending order, 78.09 points for abemaciclib, 78.04 points for palbociclib, 72.15 points for dalpiciclib, and 69.24 points for ribociclib by integrating the result of the 5 dimensions. Conclusion: Until the clinical studies, guideline recommendations, prices, and many other aspects of this assessment are updated, abemaciclib and palbociclib, which have the top 2 scores, can be used as a priority recommendation for Chinese medical institutions to select CDK4/6 inhibitors and optimize the use of the drug catalog based on the scoring results of this assessment.

show abstract

Immunomodulatory effects of CDK4/6 inhibitors

Cited by 10 publications

References 99 publications

The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays

The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays

Spatiotemporally Controlled T‐Cell Combination Therapy for Solid Tumor

CDK4/6 inhibitors for hormone receptor-positive/human epidermal growth factor receptor 2 negative advanced breast cancer: A rapid health technology assessment

Contact Info

Product

Resources

About