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Updated: Jul 2, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Deterministic reprogramming and signaling activation following targeted therapy in non-small cell lung cancer driven
Rafael Rosell1,2, Carlos Pedraz-Valdunciel3, Anisha Jain4
1Cancer Biology & Precision Medicine Program, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.
Introduction:
Targeted therapy is used to treat lung adenocarcinoma caused by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain and rare subtypes (<5%) of non-small cell lung cancer. These subtypes include fusion oncoproteins like anaplastic lymphoma kinase (ALK), ROS1, rearranged during transfection (RET), and other receptor tyrosine kinases (RTKs). The use of diverse selective oral inhibitors, including those targeting rat sarcoma viral oncogene homolog (KRAS) mutations, has significantly improved clinical responses, extending progression-free and overall survival.
Areas Covered:
Resistance remains a critical issue in lung adenocarcinoma, notably in EGFR mutant, echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion, and KRAS mutant tumors, often associated with epithelial-to-mesenchymal transition (EMT).
Expert Opinion:
Despite advancements in next generation EGFR inhibitors and EML4-ALK therapies with enhanced brain penetrance and identifying resistance mutations, overcoming resistance has not been abated. Various strategies are being explored to overcome this issue to achieve prolonged cancer remission and delay resistance. Targeting yes-associated protein (YAP) and the mechanisms associated with YAP activation through Hippo-dependent or independent pathways, is desirable. Additionally, the exploration of liquid-liquid phase separation in fusion oncoproteins forming condensates in the cytoplasm for oncogenic signaling is a promising field for the development of new treatments.
Insights
Targeted therapies improve outcomes for lung adenocarcinoma with EGFR, ALK, and KRAS mutations. However, overcoming treatment resistance, possibly via YAP targeting, remains crucial for prolonged remission.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeted therapies, including oral inhibitors for epidermal growth factor receptor (EGFR) and rat sarcoma viral oncogene homolog (KRAS) mutations, have significantly improved survival in non-small cell lung cancer (NSCLC) subtypes.
- Specific NSCLC subtypes, such as those with anaplastic lymphoma kinase (ALK) fusions, are also treated with targeted agents.
- Resistance to these targeted therapies, often linked to epithelial-to-mesenchymal transition (EMT), is a major clinical challenge.
Purpose of the Study:
- To review current strategies for overcoming resistance in targeted lung adenocarcinoma therapy.
- To highlight novel therapeutic avenues, including targeting yes-associated protein (YAP) and understanding oncogenic signaling through liquid-liquid phase separation.
Main Methods:
- Literature review of targeted therapies for lung adenocarcinoma.
- Analysis of resistance mechanisms in EGFR, ALK, and KRAS-mutated lung cancers.
- Exploration of emerging therapeutic strategies and molecular targets.
Main Results:
- Despite advancements in next-generation inhibitors and therapies with improved brain penetrance, resistance remains a significant obstacle.
- Strategies to overcome resistance are actively being investigated to achieve prolonged cancer remission.
- Targeting YAP and exploring liquid-liquid phase separation in oncoprotein condensates show promise.
Conclusions:
- Overcoming resistance in targeted lung adenocarcinoma therapy is essential for improving patient outcomes.
- Targeting YAP and investigating the role of liquid-liquid phase separation in oncogenic signaling represent promising future directions for treatment development.
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