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Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting?
Venus Sosa Iglesias1, Lorena Giuranno1, Ludwig J Dubois1
1Department of Radiation Oncology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), Maastricht, Netherlands.
Abstract:
Drug resistance is a major cause for therapeutic failure in non-small cell lung cancer (NSCLC) leading to tumor recurrence and disease progression. Cell intrinsic mechanisms of resistance include changes in the expression of drug transporters, activation of pro-survival, and anti-apoptotic pathways, as well as non-intrinsic influences of the tumor microenvironment. It has become evident that tumors are composed of a heterogeneous population of cells with different genetic, epigenetic, and phenotypic characteristics that result in diverse responses to therapy, and underlies the emergence of resistant clones. This tumor heterogeneity is driven by subpopulations of tumor cells termed cancer stem cells (CSCs) that have tumor-initiating capabilities, are highly self-renewing, and retain the ability for multi-lineage differentiation. CSCs have been identified in NSCLC and have been associated with chemo- and radiotherapy resistance. Stem cell pathways are frequently deregulated in cancer and are implicated in recurrence after treatment. Here, we focus on the NOTCH signaling pathway, which has a role in stem cell maintenance in non-squamous non-small lung cancer, and we critically assess the potential for targeting the NOTCH pathway to overcome resistance to chemotherapeutic and targeted agents using both preclinical and clinical evidence.
Insights
Drug resistance in non-small cell lung cancer (NSCLC) stems from tumor heterogeneity and cancer stem cells (CSCs). Targeting the NOTCH pathway may overcome resistance to therapies, improving treatment outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Drug resistance is a primary cause of therapeutic failure in non-small cell lung cancer (NSCLC), leading to tumor recurrence and progression.
- Tumor heterogeneity, driven by cancer stem cells (CSCs), contributes to diverse responses to therapy and the emergence of resistant clones.
- CSCs are implicated in chemo- and radiotherapy resistance in NSCLC, with deregulated stem cell pathways frequently observed in cancer.
Purpose of the Study:
- To critically assess the potential of targeting the NOTCH signaling pathway to overcome drug resistance in non-small cell lung cancer.
- To investigate the role of the NOTCH pathway in stem cell maintenance in non-squamous NSCLC.
- To evaluate preclinical and clinical evidence for NOTCH pathway inhibition as a strategy against therapeutic resistance.
Main Methods:
- Review of preclinical studies investigating NOTCH pathway inhibitors in NSCLC models.
- Analysis of clinical trial data evaluating therapies targeting the NOTCH pathway.
- Assessment of the association between NOTCH signaling, CSCs, and drug resistance mechanisms in NSCLC.
Main Results:
- The NOTCH signaling pathway plays a crucial role in maintaining stemness in non-squamous NSCLC.
- Evidence suggests that targeting the NOTCH pathway can sensitize resistant NSCLC cells to chemotherapeutic and targeted agents.
- Preclinical and clinical data indicate that NOTCH pathway dysregulation contributes to therapeutic resistance.
Conclusions:
- Targeting the NOTCH signaling pathway presents a promising strategy to overcome drug resistance in non-small cell lung cancer.
- Understanding the interplay between NOTCH, CSCs, and tumor microenvironment is essential for developing effective resistance-combating therapies.
- Further clinical investigation is warranted to validate NOTCH pathway inhibition for improved NSCLC treatment outcomes.
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