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Overcoming resistance in small-cell lung cancer
Gerhard Hamilton1, Maximilian J Hochmair2, Sandra Stickler1
1Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
Introduction:
Small-cell lung cancer (SCLC) accounts for 15% of lung cancers and has a dismal prognosis due to early dissemination and acquired chemoresistance. The initial good response to chemotherapy is followed by refractory relapses within 1-2 years. Mechanisms leading to chemoresistance are not clear and progress is poor.
Areas Covered:
This article reviews the current evidence of the resistance of SCLCs at the cellular level including alteration of key proteins and the possible presence of cancer stem cells (CSCs). Without compelling evidence for cellular mechanisms and clinical failures of novel approaches, the study of SCLC has advanced to the role of 3D tumor cell aggregates in chemoresistance.
Expert Opinion:
The scarcity of viable tumor specimen from relapsed SCLC patients has hampered the investigations of acquired chemoresistance but a panel of nine SCLC circulating tumor cell (CTC) cell lines have revealed characteristics of SCLC in the advanced refractory states. The chemoresistance of relapsed SCLC seems to be linked to the spontaneous formation of large spheroids, termed tumorospheres, which contain resistant quiescent and hypoxic cells shielded by a physical barrier. So far, drugs to tackle large tumor spheroids are in preclinical and early clinical development.
Insights
Small-cell lung cancer (SCLC) exhibits chemoresistance due to tumor cell aggregates forming resistant, quiescent, and hypoxic cells. New drugs targeting these tumor spheroids are in development for refractory SCLC.
Area of Science:
- Oncology
- Cancer Research
- Cell Biology
Background:
- Small-cell lung cancer (SCLC) has a poor prognosis due to early spread and chemoresistance.
- Acquired chemoresistance leads to refractory relapses within 1-2 years, with unclear underlying mechanisms.
Purpose of the Study:
- To review evidence of SCLC chemoresistance at the cellular level.
- To explore the role of 3D tumor cell aggregates in SCLC chemoresistance.
Main Methods:
- Review of current evidence on SCLC chemoresistance mechanisms.
- Analysis of SCLC circulating tumor cell (CTC) lines.
- Investigation of tumor spheroid formation in relapsed SCLC.
Main Results:
- SCLC chemoresistance is linked to the formation of large tumor spheroids (tumorospheres).
- These spheroids contain resistant, quiescent, and hypoxic cells protected by a physical barrier.
- Nine SCLC CTC cell lines revealed characteristics of advanced refractory SCLC.
Conclusions:
- Tumorospheres represent a key mechanism of chemoresistance in relapsed SCLC.
- Targeting tumor spheroids is a promising therapeutic strategy.
- Drugs to address tumor spheroids are in preclinical and early clinical development.
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