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Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights
Catherine B Meador1, Aaron N Hata2
1Massachusetts General Hospital Cancer Center, Charlestown, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA.
Abstract:
While significant advancements have been made in the available therapies for metastatic non-small cell lung cancer (NSCLC), acquired resistance remains a major barrier to treatment. We have not yet achieved the ability to cure advanced NSCLC with systemic therapy, despite our growing understanding of many of the oncogenic drivers of this disease. Rather, the emergence of drug-tolerant and drug-resistant cells remains the rule, even in the face of increasingly potent targeted therapies. In this review, we provide a broad overview of the mechanisms of resistance to targeted therapy that have been demonstrated across molecular subtypes of NSCLC, highlighting the dynamic interplay between driver oncogene, bypass signaling pathways, shifting cellular phenotypes, and surrounding tumor microenvironment.
Insights
Acquired resistance to targeted therapies is a major challenge in treating metastatic non-small cell lung cancer (NSCLC). Understanding resistance mechanisms is key to improving outcomes for advanced NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Metastatic non-small cell lung cancer (NSCLC) treatments have advanced, but acquired resistance limits cure potential.
- Drug-tolerant and resistant cells emerge despite potent targeted therapies, hindering treatment efficacy.
- Understanding oncogenic drivers in advanced NSCLC is crucial but insufficient for systemic cure.
Purpose of the Study:
- To provide a comprehensive review of resistance mechanisms to targeted therapy in NSCLC.
- To explore resistance across diverse molecular subtypes of NSCLC.
- To highlight the complex interactions influencing treatment failure.
Main Methods:
- Literature review of published studies on targeted therapy resistance in NSCLC.
- Analysis of molecular subtypes and their associated resistance pathways.
- Examination of cellular phenotypes and tumor microenvironment factors.
Main Results:
- Resistance mechanisms vary significantly across different molecular subtypes of NSCLC.
- Bypass signaling pathways and altered cellular phenotypes contribute to acquired resistance.
- The tumor microenvironment plays a dynamic role in the development of drug resistance.
Conclusions:
- Targeted therapies for NSCLC face significant hurdles due to acquired resistance.
- A deeper understanding of the interplay between driver oncogenes, bypass pathways, and the microenvironment is essential.
- Future strategies must address these multifaceted resistance mechanisms for improved NSCLC treatment.
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