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Expression of large tumour suppressor (LATS) kinases modulates chemotherapy response in advanced non-small cell lung cancer.

ABSTRACT: Background:The Hippo signalling pathway plays an important role in regulating organ size and cell proliferation. Down-regulation of large tumour suppressor (LATS) protein homologs LATS1 or LATS2 has been found in lung cancer. LATS1 and LATS2 are the core components of the Hippo signalling pathway. LATS1 and LATS2 share some conserved structural features and exhibit redundant biological functions. The aim of this study was to dissect the interaction between these two homologs. Methods:In lung adenocarcinoma (AD) cells, protein expression of LATS1 and LATS2 were determined by western blotting; cell viability and apoptosis were measured by MTT and annexin V staining after treatment with cisplatin; subcellular distributions of LATS proteins were determined by immunofluorescence microscopy; LATS2 expression was modulated by shRNA-mediated knockdown or ectopic expression in cancer cell lines. Results:Manipulation of the expression of these two LATS kinases influenced cisplatin response in advanced lung AD cell lines. High LATS2-to-LATS1 ratio in H2023 cells was associated with cisplatin resistance, while low LATS2-to-LATS1 ratio in CL1-0 and CL83 cells was associated with sensitivity to cisplatin. Manipulating the LATS2-to-LATS1 ratio by LATS2 over-expression in CL1-0 and CL83 rendered them resistant to cisplatin treatment, whereas LATS2 knockdown in H2023 alleviated the LATS2-to-LATS1 ratio and sensitized cancer cells to cisplatin exposure. Conclusions:Our data suggested that the ratio of expression of LATS kinases played a role in the modulation of cisplatin sensitivity in advanced lung AD, and targeting of LATS proteins as a novel therapeutic strategy for lung AD deserves further investigation.

SUBMITTER: Luo SY

PROVIDER: S-EPMC7225163 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Expression of large tumour suppressor (LATS) kinases modulates chemotherapy response in advanced non-small cell lung cancer.

Luo Susan Yang SY Kwok Hoi-Hin HH Yang Pan-Chyr PC Ip Mary Sau-Man MS Minna John Dorrance JD Lam David Chi-Leung DC

Translational lung cancer research 20200401 2

<h4>Background</h4>The Hippo signalling pathway plays an important role in regulating organ size and cell proliferation. Down-regulation of large tumour suppressor (LATS) protein homologs LATS1 or LATS2 has been found in lung cancer. LATS1 and LATS2 are the core components of the Hippo signalling pathway. LATS1 and LATS2 share some conserved structural features and exhibit redundant biological functions. The aim of this study was to dissect the interacti ...[more]

PMID: 32420069

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Project description:BackgroundWhether a combination of chemotherapy and erlotinib is beneficial for advanced non-small cell lung cancer (NSCLC) remains controversial. This study aimed to summarize the currently available evidence and compare the efficacy and safety of chemotherapy plus erlotinib versus chemotherapy alone for treating advanced NSCLC.MethodsEMBASE, PubMed, and the Cochrane Central Register of Controlled Trials were searched for relevant studies. Our protocol was registered in PROSPERO (CRD42014015015).ResultsNine randomized controlled trials with a total of 3599 patients were included. Compared to chemotherapy alone, chemotherapy plus erlotinib was superior in PFS (HR = 0.76 [95% CI 0.62, 0.92], P = 0.006), and no statistically significant difference was observed in OS (HR = 0.94 [95% CI 0.86, 1.03], P = 0.16). Intercalated erlotinib plus chemotherapy demonstrated improvements in PFS (HR = 0.67 [95% CI 0.50, 0.91], P = 0.009) and OS (HR = 0.82 [95% CI 0.69, 0.98], P = 0.03). Continuous erlotinib plus chemotherapy treatment failed to demonstrate improvements in PFS (HR = 0.91 [95% CI 0.80, 1.04], P = 0.16) and OS (HR = 0.98 [95% CI 0.89, 1.09], P = 0.75). The association of chemotherapy plus erlotinib with improvement in PFS was significant in never smoking patients (HR = 0.46 [95% CI 0.37, 0.56], P<0.00001) but not in smoking patients (HR = 0.70 [95% CI 0.49, 1.00], P = 0.05). Among patients with EGFR mutant tumors, chemotherapy plus erlotinib demonstrated significant improvements in PFS (HR = 0.31 [95% CI 0.17, 0.58], P = 0.0002) and OS (HR = 0.52 [95% CI 0.30, 0.88], P = 0.01). Among patients with EGFR wild-type tumors, no statistically significant difference was observed with respect to PFS (HR = 0.87 [95% CI 0.70, 1.08], P = 0.21) and OS (HR = 0.78 [95% CI 0.59, 1.01], P = 0.06).ConclusionCombination of chemotherapy and erlotinib is a viable treatment option for patients with NSCLC, especially for patients who never smoked and patients with EGFR mutation-positive disease. In addition, intercalated administration is an effective combinatorial strategy.

Project description:Simple Summary Lung cancer that is driven by mutations in the epidermal growth factor receptor (EGFR) is currently treated with tyrosine kinase inhibitors (TKIs). Although patients initially respond well to TKI treatment, drug resistance against EGFR-targeted therapy emerges. Attempts to combine immunotherapy with EGFR-targeted treatment to prolong response rates or prevent the development of resistances have been limited due to insufficient knowledge about the effects of targeted therapy on the tumour microenvironment (TME) in EGFR-driven tumours and tumour-infiltrating immune cells. The aims of this study were to improve our understanding on the impact of EGFR inhibition on the immune response in EGFR-driven lung cancer and, furthermore, to gain insights into the impact of combining targeted therapy with immunotherapy on the TME. Abstract EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC.

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Project description:Background: The potency and safety of toripalimab combination with chemotherapy (TC) as the first-line therapy for advanced non-small cell lung cancer (NSCLC) have been demonstrated in the CHOICE-01 study. Our research explored whether TC was cost-effective compared to chemotherapy alone from the Chinese payer perspective. Materials and methods: Clinical parameters were obtained from a randomized, multicenter, registrational, placebo-controlled, double-blind, phase III trial. Standard fee databases and previously published literature were used to determine costs and utilities. A Markov model with three mutually exclusive health statuses (progression-free survival (PFS), disease progression, and death) was used to predict the disease course. The costs and utilities were discounted at 5% per annum. The main endpoints of the model included cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Univariate and probabilistic sensitivity analyses were performed to investigate the uncertainty. Subgroup analyses were performed to verify the cost-effectiveness of TC in patients with squamous and non-squamous cancer. Results: TC combination therapy yielded an incremental 0.54 QALYs with an incremental cost of $11,777, compared to chemotherapy, giving rise to ICERs of $21,811.76/QALY. Probabilistic sensitivity analysis revealed that TC was not favorable at 1 time GDP per capita. With a prespecified willingness-to-pay threshold (WTP) of three times the GDP per capita, combined treatment had a 100% probability of being cost-effective and had substantial cost-effectiveness in advanced NSCLC. Probabilistic sensitivity analyses showed that TC was more likely to be accepted with a WTP threshold higher than $22,195 in NSCLC. Univariate sensitivity analysis showed that the utility of PFS state, crossover proportions of the chemotherapy arm, cost per cycle of pemetrexed treatment, and discount rate were the dominant influencing factors. Subgroup analyses found that in patients with squamous NSCLC, the ICER was $14,966.09/QALY. In the non-squamous NSCLC, ICER raised to $23,836.27/QALY. ICERs were sensitive to the variance of the PFS state utility. TC was more likely to be accepted when WTP increases exceeded $14,908 in the squamous NSCLC subgroup and $23,409 in the non-squamous NSCLC subgroup. Conclusion: From the perspective of the Chinese healthcare system, TC may be cost-effective in individuals with previously untreated advanced NSCLC at the prespecified WTP threshold compared to chemotherapy, and more significant in individuals with squamous NSCLC, which will provide evidence for clinicians to make the best decisions in general clinical practice.

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Expression of large tumour suppressor (LATS) kinases modulates chemotherapy response in advanced non-small cell lung cancer.

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Expression of large tumour suppressor (LATS) kinases modulates chemotherapy response in advanced non-small cell lung cancer.

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