Emerging therapies for non-small cell lung cancer

Zhang, Chao; Leighl, Natasha B.; Wu, Yi‐Long; Zhong, Wen‐Zhao

doi:10.1186/s13045-019-0731-8

Cited by 122 publications

(103 citation statements)

References 251 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Lung cancer ranks first among all malignant tumors in regards to morbidity and mortality worldwide, with 2.1 million new lung cancer cases and 1.8 million deaths expected worldwide in 2018 (1). Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, and targeted therapy and immunotherapy for NSCLC treatment are developing rapidly (2,3). Accurate judgment and prognostic assessment are important factors influencing the appropriate treatment for each individual case.…”

Section: Introductionmentioning

confidence: 99%

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Zhang

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

Establishing a prognostic genetic signature closely related to the tumor immune microenvironment (TIME) to predict clinical outcomes is necessary. Using the Gene Expression Omnibus (GEO) database of a non-small cell lung cancer (NSCLC) cohort and the immune score derived from the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, we applied the least absolute shrinkage and selection operator (LASSO) Cox regression model to screen a 10-gene signature among the 448 differentially expressed genes and found that the risk prediction models constructed by 10 genes could be more sensitive to prognosis than TNM (Tumor, Lymph node and Metastasis) stage (P=0.006). The CIBERSORT method was applied to quantify the relative levels of different immune cell types. It was found that the ratio of eosinophils, mast cells (MCs) resting and CD4 T cells memory activated in the low-risk group was higher than that in the high-risk group, and the difference was statistically significant (P= 0.003, P= 0.014 and P= 0.018, respectively). Inconsistently, the ratio of resting natural killer (NK) cells and activated plasma cells in the low-risk group was significantly lower than that in the high-risk group (P= 0.05 and P=0.009, respectively). Kaplan-Meier survival results showed that patients of the high-risk group had significantly shorter overall survival (OS) than those of the low-risk group in the training set (P<0.001). Furthermore, Kaplan-Meier survival showed that patients of the high-risk group had significantly shorter OS than those of the low-risk group (P=0.0025 and P=0.0157, respectively) in the validation set [GSE31210 and TCGA (The Cancer Genome Atlas)]. The 10-gene signature was found to be an independent risk factor for prognosis in univariate and multivariate Cox proportional hazard regression analyses (P<0.001). In addition, it was found that the risk model constructed by the 10-gene signature was related to the clinical related factors in logistic regression analysis. The genetic signature closely related to the immune microenvironment was found to be able to predict differences in the proportion of immune cells (eosinophils, resting MCs, memory activated CD4 T cells, resting NK cells and plasma cells) in the risk model. Our findings suggest that the genetic signature closely related to TIME could predict the prognosis of NSCLC patients, and provide some reference for immunotherapy.

show abstract

Section: Introductionmentioning

confidence: 99%

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Zhang

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…The choice of chemotherapeutic regimen in NSCLC is mainly determined by the histological subtype and the status of genetic driver mutations [10,14]. Recently, landmark discoveries of targeted drugs [14,15] and immunotherapies [16,17] have shifted the frontline therapies towards an era of personalized medicine [5,17,18]. However, besides the high cost of therapy, the targeted drugs and immunotherapies benefit small and specific groups of NSCLC patients.…”

Section: Research Papermentioning

confidence: 99%

“…Patients are administered with four-six cycles [22] of platinumbased chemotherapy, which normally consists of a platinum compound such as cisplatin (cis-Pt) or carboplatin administered alongside a third-generation chemotherapeutic agent [10,12,21,22]. In the clinic, the taxane-platinum combinations are the standard of care treatments of advanced NSCLC [14,23]. Taxanes as a class of anticancer agents is a large group of compounds that target microtubule function during cell division [24].…”

Section: Research Papermentioning

confidence: 99%

See 1 more Smart Citation

Untitled

2020

Oncotarget

View full text Add to dashboard Cite

Platinum-taxane combination chemotherapy still represents the standard of care for advanced non-small cell lung cancer (NSCLC) with no targetable driver mutations. However, the efficacy of these drugs has plateaued at 10-14 months primarily due to dose-limiting toxicity, chemoresistance, and metastasis. Here, we explored the effects of withaferin A (WFA) alone and in combination with paclitaxel (PAC) on the growth, proliferation, migration, and invasion of human NSCLC cells. We show that the sensitivity of H1299 and A549 cells to concomitant treatment with PAC and WFA was greater than that of either PAC or WFA alone. Using the combination index and dosereduction index, we demonstrated that various combinations (1:40, 1:20, 1:10) of PAC to WFA, respectively, were highly synergistic. In addition, PAC+WFA co-treatment synergistically inhibited colony formation, migration, invasion and increased the induction of apoptosis in H1299 and A549 cells. Interestingly, the synergism of PAC and WFA was not schedule-dependent but was enhanced when cells were pretreated with WFA indicating a chemo-sensitizing effect. Importantly, WFA was active against both PAC-sensitive (TS-A549) and PAC-resistant (TR-A549) cells both in vitro and in vivo. Mechanistically, WFA inhibits the proliferation of NSCLC cells via thiol oxidation. The effects of WFA were inhibited in the presence of N-acetyl cysteine and other thiol donors. Taken together, our results demonstrate the efficacy of WFA alone or alongside PAC on NSCLC cells and provide a strong rationale for further detailed testing in clinically relevant models for the development of PAC+WFA combination as an alternative therapeutic strategy for advanced NSCLC.

show abstract

“…Regarding the druggability, since more specific and potent TKIs targeting RET such as BLU-667 and LOXO-29 2 [7][8][9] are currently not available for all of the patients, the common systemic treatment regimen now includes multikinase inhibitors (MKIs), chemotherapy, and immune checkpoint inhibitors (ICIs). The success of traditional MKIs is relatively limited [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

Dong

Zhao

et al. 2020

J Hematol Oncol

Self Cite

View full text Add to dashboard Cite

Background: Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared. Methods: Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs). Results: Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/ 53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6-39.1] vs 24.8 months [95% CI, 11.7-52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI,.9] vs 4.8 months [95% CI, 4.5-5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10).Conclusions: RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.

show abstract

Emerging therapies for non-small cell lung cancer

Cited by 122 publications

References 251 publications

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Untitled

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

Contact Info

Product

Resources

About