Therapeutic targeting of the mevalonate–geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer

Guo, Chenchen; Wan, Ruijie; He, Yayi; Lin, Shuhai; Cao, Jiayu; Qiu, Ying; Zhang, Tengfei; Zhao, Qiqi; Niu, Yujia; Jin, Yujuan; Huang, Hsin‐Yi; Wang, Xue; Li, Tan; Thomas, Roman K.; Zhang, Hua; Chen, Luonan; Wong, Kwok‐Kin; Hu, Liang; Ji, Hongbin

doi:10.1038/s43018-022-00358-1

Cited by 48 publications

(28 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More importantly, genetic backgrounds greatly diverge the evolution routes towards resistance, which means different patient may develop chemoresistance via distinct mechanisms, further complicating the choice of clinical intervention. Despite tremendous efforts on characterizing specific resistance mechanisms and developing targeting strategies accordingly 16, 21, 65, 66, 67, 68, 69, 74, 75 , the lack of effective biomarkers and prior knowledge of resistance mechanisms on the individual tumors still impede the application of patient-specific precision medicine at current stage. Therefore, seeking convergent vulnerabilities, if any, for evolutionarily distinct chemoresistance represents another important and innovative approach to develop practical therapeutics against chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer

Zhong,

Jiang,

Yao

et al. 2024

Preprint

View full text Add to dashboard Cite

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer

Zhong,

Jiang,

Yao

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…GGDPS expression was significantly increased in lung adenocarcinoma tissues compared with adjacent normal tissues, and expression level was found to correlate with indicators of disease stage such as large tumours, high TNM stage, lymph node metastasis and poor prognosis 61 . Similarly, GGDPS expression was found to be negatively associated with survival in patients with small cell lung cancer 76 …”

Section: Ggdps In Disease Statesmentioning

confidence: 98%

“… 61 Similarly, GGDPS expression was found to be negatively associated with survival in patients with small cell lung cancer. 76 …”

Section: Ggdps In Disease Statesmentioning

confidence: 99%

Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

Muehlebach

Holstein

2023

Clinical & Translational Med

View full text Add to dashboard Cite

Geranylgeranyl diphosphate synthase (GGDPS), an enzyme in the isoprenoid biosynthesis pathway, is responsible for the production of geranylgeranyl pyrophosphate (GGPP). GGPP serves as a substrate for the post‐translational modification (geranylgeranylation) of proteins, including those belonging to the Ras superfamily of small GTPases. These proteins play key roles in signalling pathways, cytoskeletal regulation and intracellular transport, and in the absence of the prenylation modification, cannot properly localise and function. Aberrant expression of GGDPS has been implicated in various human pathologies, including liver disease, type 2 diabetes, pulmonary disease and malignancy. Thus, this enzyme is of particular interest from a therapeutic perspective. Here, we review the physiological function of GGDPS as well as its role in pathophysiological processes. We discuss the current GGDPS inhibitors under development and the therapeutic implications of targeting this enzyme.

show abstract

“…Furthermore, a negative correlation was observed between GGPS1 expression and patient survival. Notably, combined statin and chemotherapy treatment has resulted in prolonged responses in relapsed SCLC patients who had previously undergone chemotherapy [130].…”

Section: Chemotherapy Sensitizationmentioning

confidence: 99%

Statins in Cancer Prevention and Therapy

Ricco

Kron

2023

Cancers

View full text Add to dashboard Cite

Statins, a class of HMG-CoA reductase inhibitors best known for their cholesterol-reducing and cardiovascular protective activity, have also demonstrated promise in cancer prevention and treatment. This review focuses on their potential applications in head and neck cancer (HNC), a common malignancy for which established treatment often fails despite incurring debilitating adverse effects. Preclinical and clinical studies have suggested that statins may enhance HNC sensitivity to radiation and other conventional therapies while protecting normal tissue, but the underlying mechanisms remain poorly defined, likely involving both cholesterol-dependent and -independent effects on diverse cancer-related pathways. This review brings together recent discoveries concerning the anticancer activity of statins relevant to HNC, highlighting their anti-inflammatory activity and impacts on DNA-damage response. We also explore molecular targets and mechanisms and discuss the potential to integrate statins into conventional HNC treatment regimens to improve patient outcomes.

show abstract

Therapeutic targeting of the mevalonate–geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer

Cited by 48 publications

References 67 publications

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer

Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

Statins in Cancer Prevention and Therapy

Contact Info

Product

Resources

About