The LKB1 tumor suppressor is often mutationally inactivated in non-small cell lung cancer (NSCLC). LKB1 phosphorylates and activates members of the AMPK family of Ser/Thr kinases. Within this family, the salt-inducible kinases (SIKs) modulate gene expression in part via the inhibitory phosphorylation of the CRTCs, coactivators for CREB (cAMP response element-binding protein). The loss of LKB1 causes SIK inactivation and the induction of the CRTCs, leading to the up-regulation of CREB target genes. We identified CRTC2 as a critical factor in LKB1-deficient NSCLC. CRTC2 is unphosphorylated and therefore constitutively activated in LKB1-mutant NSCLC, where it promotes tumor growth, in part via the induction of the inhibitor of DNA binding 1 (ID1), a bona fide CREB target gene. As ID1 expression is up-regulated and confers poor prognosis in LKB1-deficient NSCLC, our results suggest that small molecules that inhibit CRTC2 and ID1 activity may provide therapeutic benefit to individuals with NSCLC.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656544PMC
http://dx.doi.org/10.1126/sciadv.aaw6455DOI Listing

Publication Analysis

Top Keywords

non-small cell
8
cell lung
8
lung cancer
8
creb target
8
lkb1-deficient nsclc
8
nsclc
5
creb
4
creb coactivator
4
crtc2
4
coactivator crtc2
4

Similar Publications

Combining radiotherapy with targeted therapy benefits patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer (EGFRm NSCLC). However, the optimal strategy to combine EGFR tyrosine kinase inhibitors (TKIs) with radiotherapy for maximum efficacy and minimal toxicity is still uncertain. Notably, EVs, which serve as communication mediators among tumor cells, play a crucial role in the anti-tumor immune response.

View Article and Find Full Text PDF

Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer and poses a significant public health challenge. Early detection is crucial for improving patient outcomes, with serum biomarkers such as carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCAg), and cytokeratin fragment 19 (CYFRA 21-1) playing a critical role in early screening and pathological classification of NSCLC. However, due to being mainly based on corresponding antibody binding reactions, existing detection technologies for these serum biomarkers have shortcomings such as complex operations, high false positive rates, and high costs.

View Article and Find Full Text PDF

Here, we report on the synthesis and biological evaluation of a novel peptide-drug conjugate, P6-SN38, which consists of the EGFR-specific short cyclic peptide, P6, and the Topo I inhibitor SN38, which is a bioactive metabolite of the anticancer drug irinotecan. SN38 is attached to the peptide at position 20 of the E ring's tertiary hydroxyl group via a mono-succinate linker. The developed peptide-drug conjugate (PDC) exhibited sub-micromolar anticancer activity on EGFR-positive (EGFR+) cell lines but no effect on EGFR-negative (EGFR-) cells.

View Article and Find Full Text PDF

Mesoporous Polydopamine Nano-Bowls Demonstrate a High Entrapment Efficiency and pH-Responsive Release of Paclitaxel for Suppressing A549 Lung Cancer Cell Proliferation In Vitro.

Pharmaceutics

December 2024

Wits Advanced Drug Delivery Platform, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.

The effectiveness of paclitaxel (PTX) in treating non-small-cell lung carcinoma (NSCLC) is restricted by its poor pharmacokinetic profile and side effects. This limitation stems from the lack of a suitable delivery vector to efficiently target cancer cells. Therefore, there is a critical need to develop an efficient carrier for the optimised delivery of PTX in NSCLC therapy.

View Article and Find Full Text PDF

Recent advancements in cancer treatment have shown the potential of immune checkpoint blockade (ICB) plus L. therapy in improving survival rates for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). The objective of this study was to investigate factors associated with improved survival in NSCLC patients treated with a combination of ICB and abnobaViscum.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!