bims-meluca 2022-09-11 papers

Oncogene. 2022 Sep 05.

ALK fusion promotes metabolic reprogramming of cancer cells by transcriptionally upregulating PFKFB3.

Mengnan Hu, Ruoxuan Bao, Miao Lin, Xiao-Ran Han, Ying-Jie Ai, Yun Gao, Kun-Liang Guan, Yue Xiong, Hai-Xin Yuan.

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase of the insulin receptor kinase subfamily, is activated in multiple cancer types through translocation or overexpression. Although several generations of ALK tyrosine kinase inhibitors (TKIs) have been developed for clinic use, drug resistance remains a major challenge. In this study, by quantitative proteomic approach, we identified the glycolytic regulatory enzyme, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), as a new target of ALK. Expression of PFKFB3 is highly dependent on ALK activity in ALK+ anaplastic large cell lymphoma and non-small-cell lung cancer (NSCLC) cells. Notably, ALK and PFKFB3 expressions exhibit significant correlation in clinic ALK+ NSCLC samples. We further demonstrated that ALK promotes PFKFB3 transcription through the downstream transcription factor STAT3. Upregulation of PFKFB3 by ALK is important for high glycolysis level as well as oncogenic activity of ALK+ lymphoma cells. Finally, targeting PFKFB3 by its inhibitor can overcome drug resistance in cells bearing TKI-resistant mutants of ALK. Collectively, our studies reveal a novel ALK-STAT3-PFKFB3 axis to promote cell proliferation and tumorigenesis, providing an alternative strategy for the treatment of ALK-positive tumors.

DOI: https://doi.org/10.1038/s41388-022-02453-0

Horm Metab Res. 2022 Sep;54(9): 604-612

Geriatric Nutritional Risk Index as a Prognostic Factor of Patients with Non-Small Cell Lung Cancer: A Meta-Analysis.

Ming Yang, Zhaohui Liu, Guojing Li, Bing Li, Chao Li, Lianbo Xiao, Jiwu Zhou.

Geriatric nutritional risk index (GNRI), a newly developed indicator of nutritional status retrieved by serum albumin concentration and ideal body weight, has been suggested as a prognostic factor for various malignancies. The aim of the study was to summarize the prognostic role of GNRI for patients with non-small cell lung cancer (NSCLC) in a meta-analysis. Cohort studies evaluating the relationship between GNRI at baseline and survival OF NSCLC were retrieved by search of PubMed, Embase, and Web of Science databases from inception to January 12, 2022. A conservative random-effect model incorporating the possible influence of between-study heterogeneity was used to pool the results. Eleven cohorts including 2865 patients with NSCLC were included. Compared to those with higher GNRI, NSCLC patients with lower GNRI were associated with poorer overall survival [OS, hazard ratio (HR): 2.39, 95% CI: 1.97-2.91, p<0.001; I2=29%), progression-free survival (HR: 1.94, 95% CI: 1.52-2.47, p<0.001; I2=29%), and cancer-specific survival (HR: 2.59, 95% CI: 1.55-4.35, p<0.001; I2=0%). Subgroup analyses showed that the significant association between lower GNRI and worse OS in patients with NSCLC was not affected by study characteristics including study location, design, cancer stage, treatment, or follow-up durations (p for subgroup effects all<0.001). In conclusion, a lower GNRI in patients with NSCLC may be a predictor of poor survival. Nutritional status indicated by GNRI may be important for the prognostic prediction of patients with NSCLC.

DOI: https://doi.org/10.1055/a-1903-1943

J Clin Pharmacol. 2022 Sep 09.

Thyroid Dysfunction in Non-Small Cell Lung Cancer With Immune Checkpoint Inhibitors: A Meta-Analysis.

Lanlan Lin, Fan Yang, Guofu Lin, Xiangqi Chen.

Immune checkpoint inhibitors (ICIs) have been established as the cornerstone for advanced non-small cell lung cancer, while thyroid adverse events (AEs) associated with ICIs have not been systematically documented. Therefore, we performed a meta-analysis to evaluate the effect of ICI applications on the thyroid of patients with non-small cell lung cancer. We performed a systematic search of PubMed, the Cochrane Library, Web of Science, and Embase for eligible randomized controlled trials up to November 2021. Clinical trials reporting thyroid AEs including hypothyroidism, hyperthyroidism, and thyroiditis were enrolled. The I2 statistic was also calculated to quantify the heterogeneity. Data were evaluated as risk ratio (RR) and corresponding 95%CIs. A total of 10 randomized clinical trials involving 6154 patients were included in this meta-analysis. ICI application was found to have a statistically significant higher risk of all grade hypothyroidism (RR, 7.03; P < .0001), hyperthyroidism (RR, 4.88; P < .0001), and thyroiditis (RR, 6.58; P = .0014) compared with the chemotherapy group. Moreover, we demonstrated that second-line therapy significantly increased the risk of all-grade hypothyroidism (RR, 7.03 [95%CI, 4.69-10.55]) and hyperthyroidism (RR, 4.88 [95%CI, 3.11-7.65]). Our meta-analysis manifested that regimens with ICIs may significantly increase all grades of hypothyroidism, hyperthyroidism, and thyroiditis. ICIs may certainly induce the occurrence and exacerbation of endocrine AEs compared with chemotherapy. This article is protected by copyright. All rights reserved.

Keywords: CTLA-4 inhibitors; PD-1/PD-L1 inhibitors; non-small cell lung cancer; thyroid adverse events

DOI: https://doi.org/10.1002/jcph.2150