Synergistic combination of cytotoxic chemotherapy and cyclin‐dependent kinase 4/6 inhibitors in biliary tract cancers

Arora, Mansi; Bogenberger, James M; Abdelrahman, Amro M.; Yonkus, Jennifer A.; Alva-Ruiz, Roberto; Leiting, Jennifer L.; Chen, Xianfeng; Usón, Pedro Luiz Serrano; Dumbauld, Chelsae; Baker, Alex; Gamb, Scott I.; Egan, Jan B.; Zhou, Yumei; Nagalo, Bolni Marius; Meurice, Nathalie; Eskelinen, Eeva‐Liisa; Salomao, Marcela A.; Kosiorek, Heidi E.; Braggio, Esteban; Barrett, Michael T.; Buetow, Kenneth H.; Sonbol, Mohamad Bassam; Mansfield, Aaron S.; Roberts, Lewis R.; Bekaii‐Saab, Tanios; Ahn, Daniel H.; Truty, Mark J.; Borad, Mitesh J.

doi:10.1002/hep.32102

Cited by 7 publications

(4 citation statements)

References 50 publications

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“…injection of 100 mg/kg ketamine: 10 mg/kg xylazine. GEM/CIS (20 mg/kg/2.5 mg/kg dose) ( 23 ) treatment was administered via intraperitoneal injection twice a week, and LCL161 (10 mg/kg dose) ( 24 ) was administered via I.P. injection every two days.…”

Section: Methodsmentioning

confidence: 99%

Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma

Prasopporn

Suppramote²,

Ponvilawan³

et al. 2022

Front. Oncol.

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Cholangiocarcinoma (CCA) is a highly lethal gastrointestinal malignancy that has one of the worst prognoses among solid tumors. The combination of Gemcitabine + Cisplatin (GEM/CIS) remains the standard first-line treatment for advanced stage CCA. However, this drug combination yields only a modest objective response rate, and in cases that initially respond to this treatment, drug resistance commonly rapidly develops. To improve the efficiency of GEM/CIS therapy for CCA, a thorough understanding of the mechanism of GEM/CIS resistance in CCA is required. To that end – in this study, we developed several acquired GEM/CIS-resistant CCA cell lines and we screened those cell lines for acquired vulnerability. The screening process revealed that subset of CCA with GEM/CIS resistance acquired vulnerability to the small-molecule second mitochondrial-derived activator of caspases (SMAC) mimetics LCL161 and Birinapant. The observed acquired vulnerability was found to be associated with upregulation of an inhibitor of apoptosis protein 2 (cIAP2), a known target of SMAC mimetics. LCL161 or cIAP2-shRNA downregulated cIAP2 and restored the sensitivity to GEM/CIS in GEM/CIS-resistant CCA cell lines and in in vivo GEM/CIS-resistant xenograft models. A strong synergic effect was observed when LCL161 was added to GEM/CIS. Interestingly, this synergism was also observed in drug-naïve CCA cell lines, xenografts, and patient-derived organoids. This triplet therapy also prevented the emergence of multidrug-resistant CCA in in vitro and in vivo models. Our findings suggest that activation of cIAP2 allows CCA to escape GEM/CIS, and that suppression of cIAP2 reestablishes the apoptotic profile of CCA, thus restoring its vulnerability to GEM/CIS. The results of this study indicate that combining the SMAC mimetic LCL161 with GEM/CIS inhibits and prevents the emergence of multidrug resistance in CCA.

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Section: Methodsmentioning

confidence: 99%

Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma

Prasopporn

Suppramote²,

Ponvilawan³

et al. 2022

Front. Oncol.

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“…These alterations accelerate tumor cell transition from G1 to S phase and result in uncontrolled cell proliferation [11][12][13][14]. Three CDK4/6 inhibitors (abemaciclib, ABE; ribociclib, RIB; palbociclib, PAL) have been approved for the treatment of hormone-receptor-positive, HER2-negative, advanced breast cancer and more CDK4/6 inhibitors have entered clinical trials for the treatment of various cancer types [15][16][17][18][19]. Nevertheless, few preclinical investigations and clinical trials of CDK4/6 inhibitors have been performed on GC patients, and thus a comprehensive inspection of the pharmacological effect of CDK4/6 inhibitors in GC remains lacking.…”

Section: Introductionmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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Background Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors. Methods Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models. Results We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models. Conclusion This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.

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“…Therefore, while performing in-depth research and development of CDK inhibitors and conducting clinical studies, the occurrence and development of drug resistance in tumors related to treatment with CDK inhibitors should also be examined with the aim of achieving improved use of this type of antineoplastic drug in the clinic. Therefore, some studies have focused on the combined use of CDK inhibitors with other targeted therapies or cytotoxic chemotherapy. − Some known first- or second-generation pan-CDK inhibitors are still undergoing clinical development. These inhibitors do not show significant clinical activity as single agents but are being re-evaluated in combination with other targeted treatments in different human research studies.…”

Section: Discussionmentioning

confidence: 99%

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

et al. 2022

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Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or have undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure–activity relationships, and efficacy performances of these selective or nonselective CDK inhibitors. The theoretical basis of early broad-spectrum CDK inhibitors is similar to the scope of chemotherapy, but because their toxicity is greater than the benefit, there is no clinical therapeutic window. The notion that selective CDK inhibitors have a safer therapeutic potential than pan-CDK inhibitors has been widely recognized during the research process. Four CDK4/6 inhibitors have been approved for the treatment of breast cancer or for prophylactic administration during chemotherapy to protect bone marrow and immune system function. Furthermore, the emerging strategies in the field of CDK inhibitors are summarized briefly, and CDKs continue to be widely pursued as emerging anticancer drug targets for drug discovery.

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Synergistic combination of cytotoxic chemotherapy and cyclin‐dependent kinase 4/6 inhibitors in biliary tract cancers

Cited by 7 publications

References 50 publications

Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma

Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

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