Combination Therapies with CDK4/6 Inhibitors to Treat <i>KRAS-</i>Mutant Pancreatic Cancer

Goodwin, Craig M.; Waters, Andrew M.; Klomp, Jennifer E.; Javaid, Sehrish; Bryant, Kirsten L.; Stalnecker, Clint A.; Drizyte‐Miller, Kristina; Papke, Bjoern; Yang, Runying; Amparo, Amber M.; Ozkan-Dagliyan, Irem; Baldelli, Elisa; Calvert, Valerie; Pierobon, Mariaelena; Sorrentino, Jessica A.; Beelen, Andrew P.; Bublitz, Natalie; Lüthen, Mareen; Wood, Kris C.; Petricoin, Emanuel F.; Sers, Christine; McRee, Autumn J.; Cox, Adrienne D.; Der, Channing J.

doi:10.1158/0008-5472.can-22-0391

Cited by 48 publications

(29 citation statements)

References 61 publications

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“…Consistent with previous reports in other cancer types, treatment with a single CDK4/6 inhibitor was ineffective in many GC patients [ 58 ]. In contrast, CDK4/6 inhibitors have been found to be more effective in combination with other drugs that may potentially circumvent the limitation [ 15 , 59 – 63 ]. Thus, candidate targets were required for in combination with CDK4/6 inhibitors to enhance the effectiveness of targeted therapies in GC [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, FK228, an epigenetic eraser inhibitor (histone deacetylase inhibitor; HDACi) exhibiting anti-tumor effects against several types of solid tumors, has been shown to restrict cell proliferation and induce apoptosis in GC cells and suppress tumor growth in GC mouse models [26]. Meanwhile, taking advantage of CRISPR-Cas9 screen technique, Goodwin, C. M., et al recently also reported that HDAC loss could enhance the growth inhibitory activity of CDK4/6 inhibitors [27]. Hence, it would be interesting to examine whether a combination of epigenetic drug with CDK4/6 inhibitor could augment the antitumor efficacy and provide a more potent treatment for patients with advanced GC.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…With the use of CDK4/6 inhibitors in preclinical and clinical settings, the relationship between c-Myc and CDK4/6 has been better elucidated. Importantly, c-Myc activation is responsible for both innate [ 66 ] and induced resistance [ 67 , 68 ] to CDK4/6 inhibition therapy. Moreover, the combination of CDK4/6 inhibitors with CDK2 [ 69 , 70 ] or ERK [ 71 ] inhibition can overcome c-Myc-dependent resistance.…”

Section: Discussionmentioning

confidence: 99%

P2RX7 promotes osteosarcoma progression and glucose metabolism by enhancing c-Myc stabilization

et al. 2023

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Background Osteosarcoma is the most common malignant tumor in bone and its prognosis has reached a plateau in the past few decades. Recently, metabolic reprogramming has attracted increasing attention in the field of cancer research. In our previous study, P2RX7 has been identified as an oncogene in osteosarcoma. However, whether and how P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming remains unexplored. Methods We used CRISPR/Cas9 genome editing technology to establish P2RX7 knockout cell lines. Transcriptomics and metabolomics were performed to explore metabolic reprogramming in osteosarcoma. RT-PCR, western blot and immunofluorescence analyses were used to determine gene expression related to glucose metabolism. Cell cycle and apoptosis were examined by flowcytometry. The capacity of glycolysis and oxidative phosphorylation were assessed by seahorse experiments. PET/CT was carried out to assess glucose uptake in vivo. Results We demonstrated that P2RX7 significantly promotes glucose metabolism in osteosarcoma via upregulating the expression of genes related to glucose metabolism. Inhibition of glucose metabolism largely abolishes the ability of P2RX7 to promote osteosarcoma progression. Mechanistically, P2RX7 enhances c-Myc stabilization by facilitating nuclear retention and reducing ubiquitination-dependent degradation. Furthermore, P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming in a predominantly c-Myc-dependent manner. Conclusions P2RX7 plays a key role in metabolic reprogramming and osteosarcoma progression via increasing c-Myc stability. These findings provide new evidence that P2RX7 might be a potential diagnostic and/or therapeutic target for osteosarcoma. Novel therapeutic strategies targeting metabolic reprogramming appear to hold promise for a breakthrough in the treatment of osteosarcoma.

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“…Cyclin-dependent kinases (CDKs) 4/6 have key roles in regulating the cell cycle and can interact with KRAS through the MAPK and PI3K pathways. The inhibitors of CDK4/6 such as palbociclib can amplify the effects of G12C inhibitors [ 75 ]. A recent study showed synergy between DT2216 (a clinical-stage BCL-XL PROTAC) and sotorasib in KRAS G12C-mutated NSCLC, CRC, and pancreatic cancer preclinical models [ 76 ].…”

Section: Overcoming Drug Resistance and The Future Of Kras Targetingmentioning

confidence: 99%

Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer

O’Sullivan

Keogh

Henderson

et al. 2023

Cancers

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Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed.

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Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer

Cited by 48 publications

References 61 publications

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

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

P2RX7 promotes osteosarcoma progression and glucose metabolism by enhancing c-Myc stabilization

Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer

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