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Volume 18, Issue 2 (June-2026 2026)
Iranian Journal of Blood and Cancer 2026, 18(2): 47-55 |
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Koç A C, Khademi Siahestalkhi E, Tan S, Demiray A. Mutation-Specific Activation of YAP/TAZ in Hippo Pathway-Mediated Resistance to Sotorasib in KRAS G12C-Mutant Non-Small Cell Lung Cancer. Iranian Journal of Blood and Cancer 2026; 18 (2) :47-55
URL: http://ijbc.ir/article-1-1902-en.html
URL: http://ijbc.ir/article-1-1902-en.html
1- Department of Medical Genetics, Faculty of Medicine, Pamukkale University, Denizli, Turkey.
2- Department of Medical Genetics, Faculty of Medicine, Pamukkale University, Denizli, Turkey. ,esiahestalkhi18@posta.pau.edu.tr
2- Department of Medical Genetics, Faculty of Medicine, Pamukkale University, Denizli, Turkey. ,
Abstract: (10 Views)
Background: Drug resistance remains a critical challenge in the treatment of KRAS G12C-mutant non-small cell lung cancer (NSCLC) with sotorasib (AMG 510). Emerging evidence suggests that the activation of YAP/TAZ via Hippo signaling pathway disruption plays a pivotal role in adaptive resistance mechanisms, highlighting a potential therapeutic target.
Methods: This study investigated the role of Hippo pathway disruption in mediating resistance to sotorasib using KRAS G12C-mutant (NCI-H23) and KRAS wild-type (NCI-H1975) NSCLC cell lines. Dose-response assays were conducted to determine IC₅₀ values, while Western blot analysis assessed the expression levels of YAP/TAZ, phosphorylated YAP (Phospho-YAP, Ser127), and upstream Hippo components (MST1, MST2, LATS, and MOB) following 72 hours of treatment.
Results: Sotorasib treatment in the NCI-H23 cell line led to a significant increase in YAP/TAZ protein expression, accompanied by a marked reduction in phosphorylated YAP and upstream Hippo components, indicating robust Hippo pathway disruption. Conversely, the NCI-H1975 cell line exhibited only a modest increase in YAP/TAZ levels, with no significant alterations in phosphorylated YAP or upstream components, suggesting a mutation-specific resistance mechanism in KRAS G12C-mutant cells.
Conclusion: This study provides compelling evidence that YAP/TAZ activation contributes to drug resistance in KRAS G12C-mutant NSCLC. Targeting both KRAS and the Hippo-YAP/TAZ axis could represent a promising therapeutic strategy to overcome resistance and enhance treatment efficacy. Further studies are urgently needed to validate these findings and explore innovative combination therapies to improve clinical outcomes in resistant NSCLC.
Methods: This study investigated the role of Hippo pathway disruption in mediating resistance to sotorasib using KRAS G12C-mutant (NCI-H23) and KRAS wild-type (NCI-H1975) NSCLC cell lines. Dose-response assays were conducted to determine IC₅₀ values, while Western blot analysis assessed the expression levels of YAP/TAZ, phosphorylated YAP (Phospho-YAP, Ser127), and upstream Hippo components (MST1, MST2, LATS, and MOB) following 72 hours of treatment.
Results: Sotorasib treatment in the NCI-H23 cell line led to a significant increase in YAP/TAZ protein expression, accompanied by a marked reduction in phosphorylated YAP and upstream Hippo components, indicating robust Hippo pathway disruption. Conversely, the NCI-H1975 cell line exhibited only a modest increase in YAP/TAZ levels, with no significant alterations in phosphorylated YAP or upstream components, suggesting a mutation-specific resistance mechanism in KRAS G12C-mutant cells.
Conclusion: This study provides compelling evidence that YAP/TAZ activation contributes to drug resistance in KRAS G12C-mutant NSCLC. Targeting both KRAS and the Hippo-YAP/TAZ axis could represent a promising therapeutic strategy to overcome resistance and enhance treatment efficacy. Further studies are urgently needed to validate these findings and explore innovative combination therapies to improve clinical outcomes in resistant NSCLC.
: Original Article |
Subject:
Genetics
Received: 2026/05/3 | Accepted: 2026/06/24 | Published: 2026/06/30
Received: 2026/05/3 | Accepted: 2026/06/24 | Published: 2026/06/30
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