bims-meluca 2023-04-02 papers

Acta Pharm Sin B. 2023 Mar;13(3): 1145-1163

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer.

Juanjuan Feng, Zhengke Lian, Xinting Xia, Yue Lu, Kewen Hu, Yunpeng Zhang, Yanan Liu, Longmiao Hu, Kun Yuan, Zhenliang Sun, Xiufeng Pang.

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Keywords: Carnitine palmitoyl transferase IA; Drug resistance; KRAS-mutant lung cancer; MEK inhibitors; Metabolic rewiring; Mitochondrial oxidative phosphorylation; Pyruvate dehydrogenase complex

DOI: https://doi.org/10.1016/j.apsb.2022.10.023

NPJ Precis Oncol. 2023 Mar 25. 7(1): 33

IKKα promotes lung adenocarcinoma growth through ERK signaling activation via DARPP-32-mediated inhibition of PP1 activity.

Sk Kayum Alam, Li Wang, Zhu Zhu, Luke H Hoeppner.

Non-small cell lung cancer (NSCLC) accounts for 80-85% cases of lung cancer cases. Diagnosis at advanced stages is common, after which therapy-refractory disease progression frequently occurs. Therefore, a better understanding of the molecular mechanisms that control NSCLC progression is necessary to develop new therapies. Overexpression of IκB kinase α (IKKα) in NSCLC correlates with poor patient survival. IKKα is an NF-κB-activating kinase that is important in cell survival and differentiation, but its regulation of oncogenic signaling is not well understood. We recently demonstrated that IKKα promotes NSCLC cell migration by physically interacting with dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant, t-DARPP. Here, we show that IKKα phosphorylates DARPP-32 at threonine 34, resulting in DARPP-32-mediated inhibition of protein phosphatase 1 (PP1), subsequent inhibition of PP1-mediated dephosphorylation of ERK, and activation of ERK signaling to promote lung oncogenesis. Correspondingly, IKKα ablation in human lung adenocarcinoma cells reduced their anchorage-independent growth in soft agar. Mice challenged with IKKα-ablated HCC827 cells exhibited less lung tumor growth than mice orthotopically administered control HCC827 cells. Our findings suggest that IKKα drives NSCLC growth through the activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity.

DOI: https://doi.org/10.1038/s41698-023-00370-3

Front Nutr. 2023 ;10 1113875

Prognostic value of sarcopenia in patients with lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors or immune checkpoint inhibitors.

Jiahua Lyu, Ningjing Yang, Ling Xiao, Xinyu Nie, Jing Xiong, Yudi Liu, Min Zhang, Hangyue Zhang, Cunhan Tang, Shiyi Pan, Long Liang, Hansong Bai, Churong Li, Hao Kuang, Tao Li.

Objectives: It remains controversial whether sarcopenia has any significant impact on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). Therefore, in this study, we aimed to assess the association between sarcopenia and clinical outcomes in patients with advanced NSCLC receiving EGFR-TKIs or ICIs as a first-line therapy.
Methods: We retrospectively enrolled 131 patients with advanced NSCLC treated with first-line EGFR-TKIs or ICIs between 1 March 2019 and 31 March 2021. To estimate sarcopenia, we calculated skeletal muscle index (SMI) as the ratio of skeletal muscle area (cm2) to height squared (m2). Associations between sarcopenia and overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and log-rank tests, respectively. A Cox proportional hazards regression model was used to assess the factors associated with OS and PFS. The Student's t-test or Mann-Whitney U test was used to compare the SMI between patients with or without objective response and disease control. The chi-squared test was used to compare adverse events (AEs) between patients with and without sarcopenia.
Results: Among the 131 patients, 35 (26.7%) were diagnosed with sarcopenia. Sarcopenia was an independent predictor of poor OS and PFS (p < 0.05) overall and in the EGFR-TKI- and ICI-treated cohorts. Among all patients, those with sarcopenia showed significantly shorter OS and PFS than those without sarcopenia (median OS and PFS: 13.0 vs. 26.0 months and 6.4 vs. 15.1 months; both p < 0.001). These associations were consistent across the subtypes of most clinical characteristics. Statistically significant differences between the objective response (OR) and non-OR groups were also observed in the mean SMI (OR group, 43.89 ± 7.55 vs. non-OR group, 38.84 ± 7.11 cm2/m2; p < 0.001). In addition, we observed similar results with disease control (DC) and non-DC groups (DC group, 42.46 ± 7.64 vs. non-DCR group, 33.74 ± 4.31 cm2/m2; p < 0.001). The AEs did not differ significantly between the sarcopenia and non-sarcopenia groups.
Conclusion: Sarcopenia before treatment might be a significant predictor of poor clinical outcomes (shorter OS and PFS, fewer ORs, less DC) in patients with advanced NSCLC treated with EGFR-TKIs or ICIs as the first-line therapy.

Keywords: EGFR-TKIs; immune-checkpoint inhibitors; lung cancer; prognosis; sarcopenia

DOI: https://doi.org/10.3389/fnut.2023.1113875

Nutrients. 2023 Mar 19. pii: 1477. [Epub ahead of print]15(6):

Diet as a Factor Supporting Lung Cancer Treatment-A Systematic Review.

Jacek Polański, Natalia Świątoniowska-Lonc, Sylwia Kołaczyńska, Mariusz Chabowski.

The purpose of this study was to summarize the evidence from epidemiological studies concerning associations between diet and the effectiveness of treatment for lung cancer. For this review, a literature search has been conducted in the EMBASE and PubMed databases, including papers published between 1977 and June 2022. The term "lung cancer" was used in conjunction with "diet". Footnotes from the selected papers were also analyzed. The present study is in line with the recommendations included in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The review included studies involving adults, including randomized controlled trials (RCTs) and cohort and observational studies. In total, 863 papers were found, with duplicates excluded. Ultimately, 20 papers were reviewed. The present systematic review indicates that vitamin A, ascorbic acid (vitamin C), vitamin E, selenium, and zinc-as antioxidants-can strengthen the body's antioxidant barrier. Furthermore, preoperative immunonutrition may not only improve perioperative nutritional status following induction chemoradiotherapy in lung cancer surgery patients but also reduce the severity of postoperative complications. Similarly, a protein supply may exert a beneficial effect on human health by increasing average body weight and muscle mass. Omega-3 fatty acid content in the diet and the consumption of their main source, fish, may have some regulatory effect on inflammation in patients with lung cancer treated with chemotherapy and radiotherapy. In addition, n-3 fatty acids inhibit tumor cell proliferation and may reduce the toxicity of chemotherapy. Increased energy and protein intake are strongly associated with improved quality of life, functional outcomes, hand grip strength, symptoms, and performance in patients with lung cancer. The use of a supportive diet should be the standard of care, alongside pharmaceutical therapy, in treatment for patients with lung cancer.

Keywords: diet; lung cancer; nutrition; outcome; treatment

DOI: https://doi.org/10.3390/nu15061477

Cells. 2023 Mar 08. pii: 832. [Epub ahead of print]12(6):

Prognostic Role of Soluble and Extracellular Vesicle-Associated PD-L1, B7-H3 and B7-H4 in Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

The treatment of non-small cell lung cancer (NSCLC) has changed dramatically with the advent of immune checkpoint inhibitors (ICIs). Despite encouraging results, their efficacy remains limited to a subgroup of patients. Circulating immune checkpoints in soluble (s) form and associated with extracellular vesicles (EVs) represent promising markers, especially in ICI-based therapeutic settings. We evaluated the prognostic role of PD-L1 and of two B7 family members (B7-H3, B7-H4), both soluble and EV-associated, in a cohort of advanced NSCLC patients treated with first- (n = 56) or second-line (n = 126) ICIs. In treatment-naïve patients, high baseline concentrations of sPD-L1 (>24.2 pg/mL) were linked to worse survival, whereas high levels of sB7-H3 (>0.5 ng/mL) and sB7-H4 (>63.9 pg/mL) were associated with better outcomes. EV characterization confirmed the presence of EVs positive for PD-L1 and B7-H3, while only a small portion of EVs expressed B7-H4. The comparison between biomarker levels at the baseline and in the first radiological assessment under ICI-based treatment showed a significant decrease in EV-PD-L1 and an increase in EV-B7H3 in patients in the disease response to ICIs. Our study shows that sPD-L1, sB7-H3 and sB7-H4 levels are emerging prognostic markers in patients with advanced NSCLC treated with ICIs and suggests potential EV involvement in the disease response to ICIs.

Keywords: B7-H3; B7-H4; NSCLC; PD-L1; extracellular vesicle; immune checkpoint inhibitors; platelets; prognosis; soluble protein

DOI: https://doi.org/10.3390/cells12060832