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Updated: Jun 13, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Is Autophagy Targeting a Valid Adjuvant Strategy in Conjunction with Tyrosine Kinase Inhibitors?
Ahmed M Elshazly1,2, Jingwen Xu3, Nebras Melhem4
1Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA.
Abstract:
Tyrosine kinase inhibitors (TKIs) represent a relatively large class of small-molecule inhibitors that compete with ATP for the catalytic binding site of tyrosine kinase proteins. While TKIs have demonstrated effectiveness in the treatment of multiple malignancies, including chronic myelogenous leukemia, gastrointestinal tumors, non-small cell lung cancers, and HER2-overexpressing breast cancers, as is almost always the case with anti-neoplastic agents, the development of resistance often imposes a limit on drug efficacy. One common survival response utilized by tumor cells to ensure their survival in response to different stressors, including anti-neoplastic drugs, is that of autophagy. The autophagic machinery in response to TKIs in multiple tumor models has largely been shown to be cytoprotective in nature, although there are a number of cases where autophagy has demonstrated a cytotoxic function. In this review, we provide an overview of the literature examining the role that autophagy plays in response to TKIs in different preclinical tumor model systems in an effort to determine whether autophagy suppression or modulation could be an effective adjuvant strategy to increase efficiency and/or overcome resistance to TKIs.
Insights
Tyrosine kinase inhibitors (TKIs) show promise in cancer treatment but face resistance. Autophagy, a cellular process, can either help tumors survive TKIs or be exploited to enhance drug efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Tyrosine kinase inhibitors (TKIs) are effective anti-cancer drugs targeting various malignancies.
- Tumor cells develop resistance to TKIs, limiting their long-term efficacy.
- Autophagy is a cellular stress response that can influence cancer cell survival.
Purpose of the Study:
- To review the role of autophagy in response to TKIs in preclinical cancer models.
- To explore whether modulating autophagy can overcome TKI resistance.
- To assess autophagy suppression or modulation as an adjuvant strategy for TKI therapy.
Main Methods:
- Literature review of preclinical studies on autophagy and TKIs.
- Analysis of tumor models investigating TKI response and autophagy.
- Evaluation of studies examining autophagy modulation in combination with TKIs.
Main Results:
- Autophagy often acts protectively, promoting tumor cell survival under TKI treatment.
- In some contexts, autophagy exhibits a cytotoxic role against cancer cells.
- The role of autophagy in TKI response varies across different tumor models.
Conclusions:
- Autophagy's dual role in TKI response necessitates careful consideration for therapeutic strategies.
- Autophagy modulation presents a potential avenue to enhance TKI efficacy and overcome resistance.
- Further research into autophagy suppression or modulation as an adjuvant to TKIs is warranted.
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