scholarly journals The Anti-Non-Small Cell Lung Cancer Cell Activity by a mTOR Kinase Inhibitor PQR620

2021 ◽  
Vol 11 ◽  
Author(s):  
Jian-hua Zha ◽  
Ying-chen Xia ◽  
Chun-lin Ye ◽  
Zhi Hu ◽  
Qin Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kinase Inhibitor ◽  
Cell Activity ◽  
Small Cell ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Mtor Kinase ◽  
Primary Nsclc ◽  
And Oxidative Stress

In non-small-cell lung carcinoma (NSCLC), aberrant activation of mammalian target of rapamycin (mTOR) contributes to tumorigenesis and cancer progression. PQR620 is a novel and highly-potent mTOR kinase inhibitor. We here tested its potential activity in NSCLC cells. In primary human NSCLC cells and established cell lines (A549 and NCI-H1944), PQR620 inhibited cell growth, proliferation, and cell cycle progression, as well as cell migration and invasion, while inducing significant apoptosis activation. PQR620 disrupted assembles of mTOR complex 1 (mTOR-Raptor) and mTOR complex 2 (mTOR-Rictor-Sin1), and blocked Akt, S6K1, and S6 phosphorylations in NSCLC cells. Restoring Akt-mTOR activation by a constitutively-active Akt1 (S473D) only partially inhibited PQR620-induced cytotoxicity in NSCLC cells. PQR620 was yet cytotoxic in Akt1/2-silenced NSCLC cells, supporting the existence of Akt-mTOR-independent mechanisms. Indeed, PQR620 induced sphingosine kinase 1 (SphK1) inhibition, ceramide production and oxidative stress in primary NSCLC cells. In vivo studies demonstrated that daily oral administration of a single dose of PQR620 potently inhibited primary NSCLC xenograft growth in severe combined immune deficient mice. In PQR620-treated xenograft tissues, Akt-mTOR inactivation, apoptosis induction, SphK1 inhibition and oxidative stress were detected. In conclusion, PQR620 exerted potent anti-NSCLC cell activity via mTOR-dependent and -independent mechanisms.

scholarly journals Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Bhaskar C. Kolla ◽  
Emilian Racila ◽  
Manish R. Patel
Keyword(s):  
Kinase Inhibitor ◽  
Small Cell Lung Carcinoma ◽  
Significant Proportion ◽  
Small Cell ◽  
Cancer Case ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Tumor Immune Evasion

Small-cell lung carcinoma (SCLC) is one of the most aggressive solid tumors, and the prognosis has not improved significantly in 25 years. Despite a recent understanding of the genomic aberrations seen in SCLC, these insights have not led to any breakthroughs in treatment. We present a patient with SCLC harboring a novel MYCL1 fusion protein who experienced a prolonged disease course due to the use of Aurora A kinase inhibitor and subsequently nivolumab. MYC family genes are master regulators of several cellular pathways including proliferation, differentiation, and apoptosis and recently have been shown to be involved in tumor immune evasion. Large studies have shown that a significant proportion of patients with SCLC have amplification or overexpression of MYC family genes. Preclinical data have exposed vulnerability of MYC-driven tumors to Aurora kinase inhibitors, bromodomain and extraterminal domain inhibitors, and recently to immune checkpoint blockers. Further studies using these agents with selective enrolling of patients with MYC-altered tumors are warranted to exploit these vulnerabilities.

scholarly journals Untargeted lipidomics of non-small cell lung carcinoma shows differentially abundant lipid classes in cancer vs non-cancer tissue

2021 ◽  
Author(s):  
Joshua M Mitchell ◽  
Robert M Flight ◽  
Andrew N Lane ◽  
Hunter N.B. Moseley
Keyword(s):  
Mass Spectrometry ◽  
Lung Cancer ◽  
Small Cell Lung Carcinoma ◽  
Treatment Options ◽  
Small Cell ◽  
Metabolic Phenotype ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Genetic Subtypes ◽  
Primary Nsclc

Lung cancer is the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) represents 85% of newly diagnosed lung cancers. The high mortality rate of lung cancer is due in part to the lack of effective treatment options for advanced disease. A major limitation in the development of effective treatment options is our incomplete understanding of NSCLC metabolism at a molecular level, especially lipids. Improvements in mass spectrometry combined with our untargeted assignment tool SMIRFE enable the systematic and less biased examination of NSCLC lipid metabolism. Lipids were extracted from paired tumorous and non-tumorous lung tissue samples from 86 patients with suspected resectable stage I or IIa primary NSCLC and were analyzed using ultra-high resolution Fourier transform mass spectrometry. Pathological examination of the samples revealed that the majority of the samples were primary NSCLC; however, the disease group does include examples of metastases of other cancers and several granulomas. Information-content-informed (ICI) Kendall tau correlation analysis revealed correlation and co-occurrence patterns consistent with significant changes in lipid profiles between disease and non-disease samples. Lipids assigned using the program SMIRFE (Mitchell et al., 2019) were analyzed for differential abundance, followed by machine learning to classify the SMIRFE formula assignments into lipid categories. At the lipid category level, sterol abundances were consistently higher in diseased versus non-diseased lung tissues at statistically significant levels. The statistically significant increase in sterol abundances in primary NSCLC compared with non-cancerous lung tissue suggests for treatment of primary NSCLC a possible therapeutic role for statins and nitrogenous bisphosphonates, pharmaceuticals that inhibit endogenous sterol biosynthesis. This hypothesis is consistent with previous epidemiological studies that have identified a therapeutic role for statins in the treatment of NSCLC but were unable to identify a molecular mechanism for this effect. Additionally, the majority of the consistently increased sterol abundances belong to the sterol ester subcategory, suggesting increased SCD1 and ACAT1 activity. SCD1 expression is a known negative prognostic indicator for survival in NSCLC. In our study, a large fraction of the NSCLC samples displayed this phenotype; however, SCD1 mutants would be unexpected in all of these samples. This suggests that this metabolic phenotype may be shared across multiple genetic subtypes of NSCLC. Thus, inhibitors of SCD1 and other enzymes involved in the production of this metabolic phenotype could have utility in the treatment of many genetic subtypes of NSCLC.

scholarly journals Long Non-Coding RNA THOR Depletion Inhibits Human Non-Small Cell Lung Cancer Cell Growth

2021 ◽  
Vol 11 ◽  
Author(s):  
Peng-Fei Jiao ◽  
Pei-jun Tang ◽  
Dan Chu ◽  
Ya-meng Li ◽  
Wei-hua Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Non Coding Rna ◽  
Primary Nsclc ◽  
Long Non Coding Rna

Long non-coding RNA (LncRNA) THOR (Lnc-THOR) is expressed in testis and multiple human malignancies. Lnc-THOR association with IGF2BP1 (IGF2 mRNA-binding protein 1) is essential for stabilization and transcription of IGF2BP1 targeted mRNAs. We tested its expression and potential functions in non-small cell lung cancer (NSCLC). In primary NSCLC cells and established cell lines, Lnc-THOR shRNA or CRISPR/Cas9-mediated knockout (KO) downregulated IGF2BP1 target mRNAs (IGF2, Gli1, Myc and SOX9), inhibiting cell viability, growth, proliferation, migration and invasion. Significant apoptosis activation was detected in Lnc-THOR-silenced/-KO NSCLC cells. Conversely, ectopic overexpression of Lnc-THOR upregulated IGF2BP1 mRNA targets and enhanced NSCLC cell proliferation, migration and invasion. RNA-immunoprecipitation and RNA pull-down assay results confirmed the direct binding between Lnc-THOR and IGF2BP1 protein in NSCLC cells. Lnc-THOR silencing and overexpression were ineffective in IGF2BP1-KO NSCLC cells. Forced IGF2BP1 overexpression failed to rescue Lnc-THOR-KO NSCLC cells. In vivo, intratumoral injection of Lnc-THOR shRNA adeno-associated virus potently inhibited A549 xenograft tumor growth in nude mice. At last we show that Lnc-THOR is overexpressed in multiple NSCLC tissues and established/primary NSCLC cells. Collectively, these results highlighted the ability of Lnc-THOR in promoting NSCLC cell growth by associating with IGF2BP1, suggesting that Lnc-THOR represents a promising therapeutic target of NSCLC.

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