ArticleOncogene2018
RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4/6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 72 citations in OpenAlex.
- A comprehensive overview of the molecular features and therapeutic targets in BRAFClinical and translational medicine · 2024Pooled it
- CDK4/6-targeted therapy for gastrointestinal cancers: from resistance mechanisms to immuno-combination strategies guided by biomarkers.Frontiers in immunology · 2026Review
- Melanoma: Pathogenesis and Targeted Therapy.MedComm · 2026Review
- Targeting the MAPK Pathway in Cancer.International journal of molecular sciences · 2025Review
- Exploring the pathway: clinical utility and open challenges of targeting BRAF alterations in biliary tract cancers and gastrointestinal malignancies.ESMO gastrointestinal oncology · 2025Review
- Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer.Nature cancer · 2025Review
- Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling.International journal of cancer · 2024Article
- Synergistic Enhancement of Antitumor Effects by Combining Abemaciclib with Desipramine.International journal of molecular sciences · 2024Article
- Targeting RAF dimers in RAS mutant tumors: From biology to clinic.Acta pharmaceutica Sinica. B · 2024Review
- Identification and validation of a glycosyltransferase gene signature as a novel prognostic model for lung adenocarcinoma.Heliyon · 2024Article
- RAF and MEK Inhibitors in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2024Review
- BRAF - a tumour-agnostic drug target with lineage-specific dependencies.Nature reviews. Clinical oncology · 2024Review
- Pharmacological modulation of RB1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- Article
- New Approaches to Targeted Therapy in Melanoma.Cancers · 2023Review
- Selected Approaches to Disrupting Protein-Protein Interactions within the MAPK/RAS Pathway.International journal of molecular sciences · 2023Review
- Developing SHP2-based combination therapy for KRAS-amplified cancer.JCI insight · 2023Article
- Molecular Pathways and Mechanisms of BRAF in Cancer Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Review
- Recent advances in targeting protein kinases and pseudokinases in cancer biology.Frontiers in cell and developmental biology · 2022Review
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer. In this study, we found that combinatory treatment with LY3009120 and abemaciclib synergistically inhibited proliferation of tumor cells in vitro and led to tumor growth regression in xenograft models with a KRAS, NRAS or BRAF mutation at the doses of two drugs that were well tolerated in combination. Further in vitro screen in 328 tumor cell lines revealed that tumor cells with KRAS, NRAS or BRAF mutation, or cyclin D activation are more sensitive, whereas tumor cells with PTEN, PIK3CA, PIK3R1 or retinoblastoma (Rb) mutation are more resistant to this combination treatment. Molecular analysis revealed that abemaciclib alone inhibited Rb phosphorylation partially and caused an increase of cyclin D1. The combinatory treatment cooperatively demonstrated more complete inhibition of Rb phosphorylation, and LY3009120 suppressed the cyclin D1 upregulation mediated by abemaciclib. These results were further verified by CDK4/6 siRNA knockdown. Importantly, the more complete phospho-Rb inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combination led to more significant cell cycle G
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