bims-meluca 2026-07-05 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–07–05
eleven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.
Clinical Outcomes Associated with Single STK11 Mutations and Those Co-occurring with KEAP1 and KRAS Mutations in Metastatic Non-Small Cell Lung Cancer.
NCAPG reprograms glycolytic and lipid metabolism by sustaining glycerophospholipid flux in small-cell lung cancer.
BAP1 Loss Might Be a Predictive Biomarker for Immunotherapy Response in Pleural Mesothelioma.
The AP2α/PDHA1 signaling pathway promotes lung cancer progression by mediating aerobic glycolysis and inhibiting cuproptosis.
Metabolic transcriptomic subtyping defines distinct immunogenomic and clinical landscapes in non-small cell lung cancer.
Obesity Promotes Lung Carcinogenesis Through Airway Immune Dysfunction.
BCAA metabolism promotes lung cancer tumorigenesis by enhancing cholesterol biosynthesis.
KLF15 activates PGC1α to rewire mitochondrial homeostasis and overcome cisplatin resistance in lung adenocarcinoma.
NRF1 Activates the AMPK/SIRT1/PGC-1α/TFAM Axis to Suppress EMT and Tumor Progression in Lung Adenocarcinoma.
The efficacy of targeted therapy in ALK-positive non-small-cell lung cancer patients and analysis of MET/PD-L1 expression status.

Science. 2026 Jul 02. 393(6806): 90-97

A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.

Michael Cross, Stefan Kotschi, Warren Wu, Fedra Luciano-Mateo, Young-Yon Kwon, Ezequiel Dantas, Taha Niazi, Shijia Chen, Ali Rashidfarrokhi, Ray Pillai, Jack Sanford, Jeshua Kim, Juliya Hsiang, Begona Gamallo-Lana, Adam C Mar, Yuan Hao, Sahith Rajalingam, Annie Huang, Jackie Shan, Habon A Issa, Maria Gomez, Alice R Wang, Xiang Zhao, Tobias Janowitz, Eileen White, Yin Liu, Kwok-Kin Wong, Leopoldo N Segal, Sheng Hui, Marcus D Goncalves, Robert C Froemke, Thales Papagiannakopoulos.

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.

DOI: https://doi.org/10.1126/science.adz4196
Adv Ther. 2026 Jun 30.

Clinical Outcomes Associated with Single STK11 Mutations and Those Co-occurring with KEAP1 and KRAS Mutations in Metastatic Non-Small Cell Lung Cancer.

Firas Dabbous, Mehmet Berktas, Rajrupa Ghosh, Samuel Huse, Ching-Yu Wang, Ashish Gautam, Kazeem Idowu, Daniel Simmons, Puneeth Iyengar.

   INTRODUCTION: Tumors with STK11 mutations and those co-occurring with KEAP1 and KRAS mutations commonly occur in patients with metastatic non-small cell lung cancer (mNSCLC). However, real-world evidence on the associated clinical outcomes is limited. This study assessed real-world progression-free survival (rwPFS) and overall survival (rwOS) among patients with mNSCLC and STK11 (co)-mutations.
METHODS: Adults (≥ 18 years old) diagnosed with de novo stage IV mNSCLC in the USA were identified from the Flatiron Clinico-Genomic Database. The frequencies of STK11 mutation and KEAP1 and KRAS co-mutations were reported. Time-to-event outcomes from mNSCLC diagnosis, including rwPFS and rwOS, were analyzed using Kaplan-Meier estimates and 95% confidence intervals (CIs). Multivariable Cox proportional hazards models assessed associations between STK11 (co)-mutations and rwOS.
RESULTS: Among 4392 patients with de novo mNSCLC, the frequencies of STK11 mutation and co-mutations in KEAP1, KRAS, and both KEAP1 and KRAS were 16.1%, 6.4%, 8.5%, and 3.7%, respectively. Compared with patients without these mutations, median rwOS was shorter in patients with STK11 mutation (8.6 vs. 12.8 months) and with co-mutations in KEAP1 (6.6 vs. 12.5 months), KRAS (10.1 vs. 12.5 months), and both KEAP1 and KRAS (5.2 vs. 12.5 months). The adjusted risk of mortality was higher in patients with STK11 co-mutations in KEAP1 (hazard ratio [HR] 1.68; 95% CI 1.29, 2.18), KRAS (HR 1.44; 95% CI 1.17, 1.76), and both KEAP1 and KRAS (HR 2.33; 95% CI 1.87, 2.90), compared with those without these mutations. Similar increased mortality risks associated with STK11 co-mutations occurred in patients with PD-L1 tumor proportion score ≥ 1% and non-squamous histology.
CONCLUSION: STK11 mutations with KEAP1 or KRAS co-mutations are associated with significantly worse survival outcomes in mNSCLC compared with patients without these co-mutations. These findings underscore the urgent need for targeted therapies to improve prognosis in this high-risk population.

Keywords:  KEAP1 mutation; KRAS mutation; Metastasis; Non-small cell lung cancer; Overall survival; PD-L1 expression; Progression-free survival; Real-world evidence; STK11 mutation; Tumor genomics

DOI:  https://doi.org/10.1007/s12325-026-03677-2
Mol Cell Biochem. 2026 Jul 01.

NCAPG reprograms glycolytic and lipid metabolism by sustaining glycerophospholipid flux in small-cell lung cancer.

Yang Sun, Jinglin Wen, Rui Su, Linlin Liu.

  Small-cell lung cancer (SCLC) is characterized by rapid growth and a pronounced neuroendocrine phenotype, accompanied by marked metabolic plasticity. Although metabolic reprogramming is a hallmark of SCLC, the molecular mechanisms coordinating glycolytic and lipid metabolic pathways remain poorly defined. Untargeted metabolomic profiling and RNA sequencing were performed on 46 surgically resected SCLC tissues, 39 paired non-tumorous lung tissues, and corresponding serum samples to identify dysregulated metabolic pathways and key regulatory genes. NCAPG expression and function were evaluated using quantitative real-time PCR, Western blotting, Seahorse extracellular flux analysis, and xenograft mouse models. Cell proliferation, apoptosis, ATP production, and reactive oxygen species (ROS) levels were quantified using standard biochemical and flow cytometric assays. Metabolomic analysis identified 438 significantly altered metabolites in SCLC, including 215 shared between tumor tissues and serum samples, indicating systemic metabolic reprogramming. Pathway enrichment analysis revealed marked activation of glycolysis, glycerophospholipid metabolism, and oxidative phosphorylation. Transcriptomic profiling identified NCAPG as one of the most upregulated genes in SCLC (fold change = 4.7, FDR < 0.001), with elevated expression associated with advanced pathological stage and poor overall survival (HR = 1.47, P = 0.002). Functional depletion of NCAPG in H69 and H446 cells reduced cell viability by 45-60% and increased apoptosis approximately twofold. Seahorse analysis demonstrated a ~ 40% reduction in extracellular acidification rate accompanied by increased oxygen consumption, indicating a metabolic shift from glycolysis toward oxidative phosphorylation. In vivo, NCAPG knockdown suppressed xenograft tumor growth by 58% and significantly downregulated key glycolytic and glycerophospholipid enzymes, including HK2, LDHA, and CHPT1. NCAPG promotes metabolic reprogramming in SCLC by sustaining coupled glycolytic and glycerophospholipid flux, thereby supporting tumor energy production and biosynthetic demands. Targeting this NCAPG-mediated metabolic axis may represent a promising therapeutic strategy for small-cell lung cancer.

Keywords:  Glycerophospholipid metabolism; Glycolysis; Metabolic reprogramming; NCAPG; Small-cell lung cancer

DOI:  https://doi.org/10.1007/s11010-026-05616-9
Thorac Cancer. 2026 Jul;17(13): e70343

BAP1 Loss Might Be a Predictive Biomarker for Immunotherapy Response in Pleural Mesothelioma.

Reina Imase, Rie Sakakibara, Susumu Kirimura, Hironori Ishibashi, Kenichi Okubo, Yasunari Miyazaki.

   INTRODUCTION: Reliable predictive biomarkers for immune checkpoint inhibitors (ICIs) in pleural mesothelioma (PM) are lacking. Loss of BRCA1-associated protein 1 (BAP1) is a frequent molecular alteration in PM and may influence the tumor immune microenvironment. We evaluated whether BAP1 loss is associated with clinical outcomes following immunotherapy.
METHODS: We retrospectively analyzed 14 patients with PM who were treated with ICIs between April 2014 and May 2024. BAP1 status was assessed by immunohistochemical staining of resected tumor specimens. Patients were categorized into BAP1-loss and BAP1-positive groups. Progression-free survival (PFS), overall survival (OS), response rate (RR), and disease control rate (DCR) were compared.
RESULTS: BAP1 loss was observed in nine patients (64%). Median PFS was significantly longer in the BAP1-loss group compared with the BAP1-positive group (5.3 vs. 2.1 months; log-rank p = 0.03). Median OS was also prolonged in the BAP1-loss group (8.6 vs. 2.1 months; log-rank p = 0.03). RR and DCR were numerically higher among patients with BAP1 loss.
CONCLUSION: BAP1 loss was associated with improved clinical outcomes following immunotherapy in PM. These findings support that a molecular profile that includes BAP1 deletion may serve as a biomarker for predicting response to immunotherapy in PM.

Keywords:  BAP1; immune checkpoint inhibitor; immunohistochemistry; immunotherapy; pleural mesothelioma

DOI:  https://doi.org/10.1111/1759-7714.70343
Exp Cell Res. 2026 Jul 02. pii: S0014-4827(26)00236-3. [Epub ahead of print] 115119

The AP2α/PDHA1 signaling pathway promotes lung cancer progression by mediating aerobic glycolysis and inhibiting cuproptosis.

Zhaowei Zheng, Qiuxia Pan, Wei Lu, Zhihao Ji, Yang Tian, Nannan Song, Jiulong Zhang, Liwen Dong, Jun Wang.

  Lung cancer poses a severe global health burden with limited effective therapeutic strategies, and dysregulated aerobic glycolysis and cuproptosis are closely linked to its progression. This study aimed to explore the role and underlying mechanism of the AP2α/PDHA1 signaling axis in lung cancer. In this research, lung cancer cell lines with stably altered AP2α and PDHA1 expression were constructed via lentivirus and shRNA transfection; rescue experiments were performed using the glycolysis inhibitor 2-deoxyglucose (2-DG) and copper chelator tetrathiomolybdate (TTM), and nude mouse xenograft models were established for in vivo verification. The results showed that AP2α was highly expressed in lung cancer, while PDHA1 was lowly expressed in lung cancer. High AP2α and low PDHA1 expression predicted poorer overall survival in lung cancer patients. Moreover, AP2α- and PDHA1-correlated genes were enriched in ATP-related biological processes, which were closely associated with aerobic glycolysis. Downregulation of AP2α suppressed cell viability, migration and invasion while inducing apoptosis, reduced aerobic glycolysis, elevated intracellular copper content and regulated key cuproptosis-related markers. Moreover, AP2α directly bound to the PDHA1 promoter. Further rescue assays confirmed that PDHA1 mediated the oncogenic effects of AP2α, and 2-DG could reverse the phenotypic changes caused by PDHA1 knockdown. In vivo experiments also validated that the AP2α/PDHA1 axis facilitated tumor growth via modulating glycolytic metabolism. Collectively, the AP2α/PDHA1 pathway may accelerate lung cancer progression by promoting aerobic glycolysis and restraining cuproptosis. This finding reveals a novel molecular mechanism of lung cancer development and provides promising targets for combined antitumor therapy.

Keywords:  AP2α; Aerobic glycolysis; Cuproptosis; Lung cancer; Metabolic reprogramming; PDHA1

DOI:  https://doi.org/10.1016/j.yexcr.2026.115119
NPJ Precis Oncol. 2026 Jul 03.

Metabolic transcriptomic subtyping defines distinct immunogenomic and clinical landscapes in non-small cell lung cancer.

Seo-Young Lee, Heesun Cheong, Seog-Yun Park, Sohyun Park, Jinju Pak, Youngjoo Lee.

This study aimed to evaluate the clinical significance of metabolic dysregulation and heterogeneity in patients with non-small cell lung cancer (NSCLC). We performed NanoString-based transcriptomic profiling of tumors from patients with advanced NSCLC receiving anti-PD-(L)1 therapy. Five distinct metabolic clusters were identified. Gene set analysis suggested differential enrichment of metabolic pathways across clusters, including immune signaling-dominant with minimal metabolic dysregulation (Cluster 1), amino acid metabolism-related (Cluster 2), hypoxia/autophagy-associated (Cluster 3), glycolytic/proliferative (Cluster 4), and mixed dysregulated metabolic features (Cluster 5). OXPHOS-related signatures were enriched in Clusters 3-5, whereas immune cell infiltration in the tumor was more prominent in Clusters 1-2. Survival outcomes differed significantly across clusters (progression-free survival, P = 0.035; overall survival, P = 0.008), with Cluster 1 showing the most favorable outcomes and Cluster 3 the worst following anti-PD-(L)1 therapy. Metabolic clusters were associated with clinicopathological and genomic features, including histology, smoking status, PD-L1 expression, and oncogenic driver alterations. In particular, RAS-RAF-MEK pathway gene alterations were more frequent in Clusters 3-5 than in Clusters 1-2. Together, metabolic transcriptomic profiling identifies clinically meaningful subtypes of NSCLC with distinct immunogenomic features and differential efficacy from anti-PD-(L)1 therapy.

DOI: https://doi.org/10.1038/s41698-026-01560-5
J Thorac Oncol. 2026 Jun 30. pii: S1556-0864(26)00519-8. [Epub ahead of print] 104066

Obesity Promotes Lung Carcinogenesis Through Airway Immune Dysfunction.

Joseph Barbi, Randall J Smith, Yeshwanth R Vedire, Deschana Washington, Robert Zollo, Sukumar Kalvapudi, Akhil Goud Pachimatla, Minyi Lee, Gang Liu, Hanqiao Liu, Robert R Vethanayagam, Nathaniel Ivanick, Mary Reid, William J Murphy, Santosh K Patnaik, Ehab Billatos, Marc E Lenburg, Jennifer Beane, Sai Yendamuri.

   RATIONALE: Despite clear links between obesity and dysfunctional anti-tumor immunity, a high Body Mass Index has been associated with decreased lung cancer risk, leading to an "Obesity Paradox".
OBJECTIVE: We sought to clarify this relationship and gain mechanistic insights using both clinical and preclinical modeling.
METHODS & MEASUREMENTS: A case control study of early-stage lung cancer risk was conducted in 1170 high-risk individuals (594 with cancer) stratified by total abdominal fat area (TFA) determined using CT scans. Airway gene expression data from 278 additional patients was analyzed as a function of TFA, and obesity's impact on chemical- and mutation-driven lung carcinogenesis models was examined. Effects on the immune contexture of murine lungs and patient broncho-alveolar lavage (n=109) were profiled using flow cytometry.
RESULTS: Lung cancer was linked to higher TFA in univariate and multivariable models. Gene expression in high-TFA airways suggested suppressed immune activity. Compared to lean controls, the lungs of obese mice displayed abundant potentially suppressive myeloid cells, activated Regulatory T cells, and effector T cell deficits at baseline and during carcinogenesis, which was significantly exacerbated by obesity. Functional assays and depletion studies suggested obesity-enhanced Tregs can potentiate rapid tumor growth, and flow analysis of patients airway leukocytes further suggest compromised lung immune surveillance in patients of high TFA.
CONCLUSIONS: Obesity is associated with enhanced lung carcinogenesis. Mechanisms of immune suppression upregulated with excess adiposity, including activated, functional Tregs, are evident in clinical and preclinical systems. These results challenge the concept of an obesity paradox for lung cancer risk.

Keywords:  Carcinogenesis; immune suppression; lung; obesity

DOI:  https://doi.org/10.1016/j.jtho.2026.104066
Cell Rep. 2026 Jul 03. pii: S2211-1247(26)00719-9. [Epub ahead of print]45(7): 117641

BCAA metabolism promotes lung cancer tumorigenesis by enhancing cholesterol biosynthesis.

Huimin Ma, Erbao Zhang, Jiaying Cai, Dong Hang, Xiaoyang Ma, Yi Yang, Meng Zhu, Qi Sun, Jianv Huang, Jing Zhang, Guang Huang, Chang Zhang, Chen Jin, Yating Fu, Lingnan Gong, Chong Shen, Xiangfeng Lu, Yue Jiang, Juncheng Dai, Guangfu Jin, Dongfeng Gu, Xu Qian, Hongbing Shen, Hongxia Ma.

  Metabolic dysregulation has been established as a key driver in tumorigenesis, but its underlying mechanisms in lung cancer remain poorly characterized. In this study, we performed nested case-control analyses in two prospective cohorts (208 and 144 matched pairs) to examine associations between plasma metabolites and lung cancer risk. Untargeted metabolomics identified circulating metabolites of the branched-chain amino acid (BCAA) pathway as significantly associated with lung cancer risk. An animal study demonstrated that a high-BCAA diet accelerated lung cancer progression in the KrasG12D/+ mice model. Among the three BCAAs, leucine contributed much more to promoting lung cancer growth. Mechanistically, AUH-mediated acetyl-CoA production from leucine metabolism fuels cholesterol synthesis, promoting lipid raft formation and EGFR redistribution and activation, thereby driving lung tumorigenesis. Moreover, atorvastatin blocked leucine-induced tumor progression in mice. Overall, our findings provide experimental evidence that leucine-driven BCAA metabolic reprogramming promotes lung tumorigenesis via cholesterol metabolism, revealing a potential therapeutic target.

Keywords:  AUH; CP: cancer; CP: metabolism; EGFR signaling; branched-chain amino acids; cholesterol; leucine; lung cancer; metabolomics; tumorigenesis

DOI:  https://doi.org/10.1016/j.celrep.2026.117641
Cell Death Discov. 2026 Jun 27.

KLF15 activates PGC1α to rewire mitochondrial homeostasis and overcome cisplatin resistance in lung adenocarcinoma.

Wan Lin, Lijuan Li, Yuwen Bai, Mai Wen, Wenjie Dong, Ruikun Ji, Jianqun Ma, Xiaodong Ling.

Cisplatin resistance represents a major barrier to effective treatment of lung adenocarcinoma (LUAD), yet its metabolic underpinnings remain incompletely defined. Here, we demonstrate that the transcription factor KLF15 governs cisplatin sensitivity by orchestrating mitochondrial biogenesis and redox homeostasis. KLF15 is downregulated in cisplatin-resistant LUAD cells, which display reduced mitochondrial content and suppressed reactive oxygen species (ROS) accumulation. Restoring KLF15 expression resensitizes LUAD cells to cisplatin both in vitro and in vivo. Mechanistically, KLF15 directly transactivates PGC1α, and loss of PGC1α abrogates KLF15-mediated cisplatin sensitization, restoring drug resistance by attenuating apoptosis. Functionally, LUAD subpopulations with low mitochondrial mass or low KLF15 expression exhibit intrinsic resistance, whereas Mito-high xenografts show enhanced therapeutic response. Together, our findings identify a KLF15-PGC1α regulatory axis that dictates mitochondrial reprogramming and cisplatin responsiveness, highlighting a potential therapeutic axis to overcome chemoresistance in LUAD.

DOI: https://doi.org/10.1038/s41420-026-03235-3
Cancer Genomics Proteomics. 2026 Jul-Aug;23(4):23(4): 806-823

NRF1 Activates the AMPK/SIRT1/PGC-1α/TFAM Axis to Suppress EMT and Tumor Progression in Lung Adenocarcinoma.

Hsing-Hsien Wu, Pei-Fang Hsieh, Ming-DER Shi, Chun-Hung Ko, Chun-Hsien Wu, Victor C Lin, Shu-Fen Liu, Yu-Ju Hung, Tzu-Sui Hung, I-Chou Wang, Yu-Lin Yang.

   BACKGROUND/AIM: Lung cancer is the leading cause of cancer-related mortality globally, emphasizing the need for identifying molecular mechanisms that drive its progression and therapeutic resistance. Nuclear respiratory factor 1 (NRF1) is a transcription factor involved in mitochondrial biogenesis, apoptosis, and epithelial-mesenchymal transition (EMT), all of which contribute to cancer initiation and metastasis. This study investigated the role of NRF1 in lung cancer progression and its potential as a therapeutic target.
MATERIALS AND METHODS: A549 lung adenocarcinoma cells were used to evaluate the effects of NRF1 overexpression (pcDNA-NRF1) and silencing (shRNA-NRF1). Moreover, western blotting were used to assess EMT markers (E-cadherin, N-cadherin, vimentin), mitochondrial biogenesis factors (T-fam), and apoptotic markers (caspase-3, caspase-9). Functional assays were performed to measure cell migration, and apoptosis. SCID mice implanted with NRF1-modified tumors were used for in vivo validation. Statistical analyses included analysis of variance (p<0.05).
RESULTS: NRF1 overexpression increased E-cadherin while reducing N-cadherin and vimentin, inhibiting EMT. It suppressed cell migration while enhancing mitochondrial biogenesis and apoptosis, as indicated by elevated caspase-3 and caspase-9 activity. Conversely, NRF1 silencing promoted EMT, reduced mitochondrial biogenesis, and decreased apoptosis. In vivo, NRF1-overexpressing tumors exhibited higher levels of E-cadherin, T-fam, and caspase-3, supporting NRF1's role in EMT suppression and mitochondrial and apoptotic pathway enhancement.
CONCLUSION: NRF1 acts as a suppressor of EMT and a promoter of mitochondrial biogenesis and apoptosis in lung cancer. Its regulatory role suggests NRF1 as a potential therapeutic target for inhibiting tumor progression and overcoming resistance to conventional therapies.

Keywords:  Lung cancer; NRF1; RNA interference; apoptosis; cell apoptosis; epithelial–mesenchymal transition; mitochondrial biogenesis; mitochondrial dysfunction; therapeutic target; tumor progression

DOI:  https://doi.org/10.21873/cgp.20602
Ther Adv Med Oncol. 2026 ;18 17588359261458657

The efficacy of targeted therapy in ALK-positive non-small-cell lung cancer patients and analysis of MET/PD-L1 expression status.

Xinyuan Wang, Yi Chen, Dong Chen, Hongyang Lu.

   Background: Anaplastic lymphoma kinase-targeted tyrosine kinase inhibitors (ALK-TKIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). However, several key issues remain unresolved. Specifically, the impact of prior chemotherapy on ALK-TKI efficacy is unclear, the impact of MET overexpression on ALK-TKI efficacy remains unclear, and the dynamic changes in programmed death ligand 1 (PD-L1) expression during the development of TKI resistance are not fully understood.
Objective: This study aimed to evaluate the efficacy of ALK-TKIs across different treatment lines, analyze the impact of MET expression on treatment outcomes, and investigate changes in PD-L1 expression before and after the development of resistance.
Design: Retrospective cohort study.
Methods: A retrospective analysis was conducted on 259 patients with ALK-positive NSCLC treated at Zhejiang Cancer Hospital between 2011 and 2022 to compare the efficacy of ALK-TKIs administered as first-line therapy versus after chemotherapy. Immunohistochemical staining was used to assess MET and PD-L1 expression. Survival analysis was performed using the Kaplan-Meier method and the log-rank test.
Results: Crizotinib showed no significant difference in progression-free survival (PFS) or overall survival (OS) between first-line and post-chemotherapy use (PFS: p = 0.803; OS: p = 0.761). For second-generation ALK-TKIs, first-line treatment had numerically longer PFS compared to post-chemotherapy (alectinib: 41 vs 24 months; ceritinib: 30 vs 8 months), but these differences were not statistically significant after adjustment (p = 0.120 and 0.284, respectively). OS did not differ significantly between the two treatment sequences for either drug. Notably, among patients treated with alectinib, those with MET overexpression had significantly shorter PFS (12 vs 42 months; p = 0.011) and OS (41 months vs not reached; p = 0.001) compared with MET-negative patients. There was no significant change in PD-L1 expression following resistance (p = 0.248).
Conclusion: ALK-TKIs have shown a tendency to improve patient survival in both first-line and post-chemotherapy settings. Among patients treated with alectinib, there appears to be a trend toward shorter PFS and OS in those with MET overexpression. In a limited number of matched samples, PD-L1 expression did not change significantly after TKI resistance, although a slight increase was observed.

Keywords:  ALK; MET; NSCLC; PD-L1; alectinib

DOI:  https://doi.org/10.1177/17588359261458657