Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in <i>PIK3CA</i>-Mutant Lung Squamous Cell Carcinoma

Shi, Ruoshi; Li, Ming; Raghavan, Vibha; Tam, Susan H.; Cabanero, Michael; Pham, Nhu-An; Shepherd, Frances A.; Moghal, Nadeem; Tsao, Ming‐Sound

doi:10.1158/1078-0432.ccr-18-0717

Cited by 18 publications

(14 citation statements)

References 48 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, a PDX model with both EGFR exon 19 deletion and T790M mutations is resistant to gefitinib/erlotinib, but responded to cetuximab (87,88 (90,91). We have also shown that lung squamous carcinoma models bearing PIK3CA E542K mutations are sensitive to PI3K inhibitors, and CDK4/6 inhibitors conferred a synergistic anti-tumor activity when used in combination with PI3K inhibitors (92). Several groups have demonstrated sensitivity of PDXs established from lung cancer patients with ALK gene rearrangement to ALK inhibitors (65,66).…”

Section: Pdx Models In Lung Cancer Researchmentioning

confidence: 73%

Patient-derived cell line, xenograft and organoid models in lung cancer therapy

Huo

D’Arcangelo

Tsao

2020

Transl Lung Cancer Res

Self Cite

View full text Add to dashboard Cite

Lung cancer accounts for most cancer-related deaths worldwide and has an overall 5-year survival rate of ~15%. Cell lines have played important roles in the study of cancer biology and potential therapeutic targets, as well as pre-clinical testing of novel drugs. However, most experimental therapies that have cleared preclinical testing using established cell lines have failed phase III clinical trials. This suggests that such models may not adequately recapitulate patient tumor biology and clinical outcome predictions.Here, we discuss and compare different pre-clinical lung cancer models, including established cell lines, patient-derived cell lines, xenografts and organoids, summarize the methodology for generating these models, and review their relative advantages and limitations in different oncologic research applications. We further discuss additional gaps in patient-derived pre-clinical models to better recapitulate tumor biology and improve their clinical predictive power.

show abstract

Section: Pdx Models In Lung Cancer Researchmentioning

confidence: 73%

Patient-derived cell line, xenograft and organoid models in lung cancer therapy

Huo

D’Arcangelo

Tsao

2020

Transl Lung Cancer Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…Another study involving more than 700 lung cancer samples reported the PIK3CA mutation frequency to be ca. 2% [63]. Kawano et al, for the first time, reported the amplification of mutant PIK3CA alleles in cancer cells [64].…”

Section: Prognostic Role Of Pik3ca Gene Mutation In Lung Cancermentioning

confidence: 99%

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

Alqahtani

Ayesh

Halawani

2019

Cancers

View full text Add to dashboard Cite

Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various significant signaling pathways. Hyperactivation of the PI3K/AKT/mTOR pathways—either via mutations or genomic amplification—confers key oncogenic activity, essential for the development and progression of several solid tumors. Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies. Although the literature reports contradictory prognostic values of PIK3CA in aggressive cancers, most of the available data highlight the important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway. Several inhibitors of PI3K/AKT/mTOR pathways are investigated as potential therapeutic options in solid malignancies. This article reviews the role of PIK3CA mutations and inhibitors of PI3K/AKT/mTOR pathways in major cancer types and examines its association with clinicopathological parameters and prognosis.

show abstract

“…Cell cycle protein CDK4 has an established association with neoplasia and cancer progression. Recent studies have found that pathways including that of CDK4/6 were frequently altered in LUSC via diverse mechanisms, suggesting CDK4/6 inhibitors as potential target for the treatment of LUSC (62,63). TPX2, which actively participates in the formation of spindle microtubules during mitosis, was significantly associated with cell differentiation and metastatic status of LUSC cells, suggesting its potential as a prognostic predictor of LUSC (64).…”

Section: Discussionmentioning

confidence: 99%

Screening and identification of key biomarkers in lung squamous cell carcinoma by bioinformatics analysis

et al. 2019

View full text Add to dashboard Cite

The high mortality rate of lung squamous cell carcinoma (LUSC) is in part due to the lack of early detection of its biomarkers. The identification of key molecules involved in LUSC is therefore required to improve clinical diagnosis and treatment outcomes. The present study used the microarray datasets GSE31552, GSE6044 and GSE12428 from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were conducted to construct the protein-protein interaction network of DEGs and hub genes module using STRING and Cytoscape. The 67 DEGs identified consisted of 42 upregulated genes and 25 downregulated genes. The pathways predicted by KEGG and GO enrichment analyses of DEGs mainly included cell cycle, cell proliferation, glycolysis or gluconeogenesis, and tetrahydrofolate metabolic process. Further analysis of the University of California Santa Cruz and ONCOMINE databases identified 17 hub genes. Overall, the present study demonstrated hub genes that were closely associated with clinical tissue samples of LUSC, and identified TYMS, CCNB2 and RFC4 as potential novel biomarkers of LUSC. The findings of the present study contribute to an improved understanding of the molecular mechanisms of carcinogenesis and progression of LUSC, and assist with the identification of potential diagnostic and therapeutic targets of LUSC.

show abstract

Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in PIK3CA-Mutant Lung Squamous Cell Carcinoma

Abstract: mutations predict response to PI3K inhibitors in LUSC. Combined PI3K and CDK4/6 inhibition enhances response to either single agents alone. Our findings provide a rationale for clinical testing of combined PI3K and CDK4/6 inhibitors in -mutant LUSC.

Cited by 18 publications

References 48 publications

Patient-derived cell line, xenograft and organoid models in lung cancer therapy

Patient-derived cell line, xenograft and organoid models in lung cancer therapy

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

Screening and identification of key biomarkers in lung squamous cell carcinoma by bioinformatics analysis

Contact Info

Product

Resources

About