The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade

Schaer, David; Beckmann, Richard P.; Dempsey, Jack; Huber, Lysiane; Forest, Amelie; Amaladas, Nelusha; Li, Yanxia; Wang, Ying Cindy; Rasmussen, Erik; Chin, Darin; Capen, Andrew; Carpenito, Carmine; Staschke, Kirk A.; Chung, Linda A.; Litchfield, Lacey M.; Merzoug, Farhana F.; Gong, Xueqian; Iversen, Philip W.; Buchanan, Sean G.; Dios, Alfonso De; Novosiadly, Ruslan D.; Kalos, Michael

doi:10.1016/j.celrep.2018.02.053

Cited by 324 publications

(305 citation statements)

References 35 publications

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“…These mechanisms are distinct from previously described immune-enhancing mechanisms of CDK4/6i (Deng et al, 2018; Goel et al, 2017) and indicate a potential role of CDK4/6, and specifically CDK4, as one of the master regulators of the program. Thus, CDK4/6i administered in a phased fashion could potentially alleviate ICI resistance in some melanoma patients, consistent with a recent observation (Schaer et al, 2018). More generally, the program’s repression in vitro could be a readout to screen for other compounds that sensitize melanoma tumors to ICI.…”

Section: Discussionsupporting

confidence: 90%

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade

Jerby‐Arnon

Shah

Cuoco

et al. 2018

Cell

945

918

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SUMMARY Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.

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Section: Discussionsupporting

confidence: 90%

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade

Jerby‐Arnon

Shah

Cuoco

et al. 2018

Cell

945

918

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“…Abemaciclib, palbociclib, and ribociclib are CDK4/6 inhibitors that have been used in hormone receptor‐positive, HER2‐negative, and advanced and metastatic BC. These drugs are always used with other inhibitors, especially AIs .…”

Section: Inhibitors For Bc and Pcmentioning

confidence: 99%

Comparison of the roles of estrogens and androgens in breast cancer and prostate cancer

Liu

Zhao

Zhang

et al. 2019

J of Cellular Biochemistry

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Breast cancer (BC) and prostate cancer (PC) are the second most common malignant tumors in women and men in western countries, respectively. The risks of death are 14% for BC and 9% for PC. Abnormal estrogen and androgen levels are related to carcinogenesis of the breast and prostate. Estradiol stimulates cancer development in BC. The effect of estrogen on PC is concentration‐dependent, and estrogen can regulate androgen production, further affecting PC. Estrogen can also increase the risk of androgen‐induced PC. Androgen has dual effects on BC via different metabolic pathways, and the role of the androgen receptor (AR) in BC also depends on cell subtype and downstream target genes. Androgen and AR can stimulate both primary PC and castration‐resistant PC. Understanding the mechanisms of the effects of estrogen and androgen on BC and PC may help us to improve curative BC and PC treatment strategies.

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“…Dosing schedules, with correlative pharmacodynamics that avoid potential feedback mechanisms, warrant further investigation.Selective CDK4/6 inhibitors together with other targeted agents or chemotherapy are also being investigated in the setting of advanced cancers 13,14. Although combination therapy has yielded better results in clinical studies performed to date, identifying the most promising and best-tolerated CDK4/6 inhibitor combination therapies is a significant challenge 46,47. In this context, the combination of SHR6390 with endocrine therapy, including tamoxifen and fulvestrant, exerted synergistic antitumor activity in ER-positive breast cancer compared with each monotherapy.…”

mentioning

confidence: 99%

Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Long

et al. 2019

Cancer Science

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Inhibition of the cyclin‐dependent kinase (CDK) 4/6‐retinoblastoma (RB) pathway is an effective therapeutic strategy against cancer. Here, we performed a preclinical investigation of the antitumor activity of SHR6390, a novel CDK4/6 inhibitor. SHR6390 exhibited potent antiproliferative activity against a wide range of human RB‐positive tumor cells in vitro, and exclusively induced G 1 arrest as well as cellular senescence, with a concomitant reduction in the levels of Ser780‐phosphorylated RB protein. Compared with the well‐known CDK4/6 inhibitor palbociclib, orally administered SHR6390 led to equivalent or improved tumor efficacy against a panel of carcinoma xenografts, and produced marked tumor regression in some models, in association with sustained target inhibition in tumor tissues. Furthermore, SHR6390 overcame resistance to endocrine therapy and HER2‐targeting antibody in ER‐positive and HER2‐positive breast cancer, respectively. Moreover, SHR6390 combined with endocrine therapy exerted remarkable synergistic antitumor activity in ER‐positive breast cancer. Taken together, our findings indicate that SHR6390 is a novel CDK4/6 inhibitor with favorable pharmaceutical properties for use as an anticancer agent.

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The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade

Cited by 324 publications

References 35 publications

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade

Comparison of the roles of estrogens and androgens in breast cancer and prostate cancer

Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

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