Inhibition of adaptive therapy tolerance in cancer: is triplet mitochondrial targeting the key?
1Turku Bioscience Centre, University of Turku and Åbo Akademi University, Finland.
Abstract:
Targeted therapies have become a mainstay in the treatment of cancer, but their long-term efficacy is compromised by acquired drug resistance. Acquired therapy resistance develops via two phases-first through adaptive development of nongenetic drug tolerance, which is followed by stable resistance through the acquisition of genetic mutations. Drug tolerance has been described in practically all clinical cancer treatment contexts, and detectable drug-tolerant tumors are highly associated with treatment relapse and poor survival. Thereby, novel therapeutic strategies are needed to overcome cancer therapy tolerance. Recent studies have identified a critical role of mitochondrial mechanisms in defining cancer cell sensitivity to targeted therapies and the surprising effects of established cancer therapies on mitochondria. Here, these recent studies are reviewed emphasizing an emerging concept of triplet therapies including three compounds targeting different cancer cell vulnerabilities but including at least one compound that targets the mitochondria. These mitochondria-targeting triplet therapies have very promising preclinical effects in overcoming cancer therapy tolerance. Potential strategies of how to overcome challenges in the clinical translation of mitochondria-targeting triplet therapies are also discussed.
Insights
New triplet therapies targeting cancer cell mitochondria show promise in overcoming drug resistance. These novel strategies aim to improve long-term cancer treatment efficacy by addressing drug tolerance and genetic mutations.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Acquired drug resistance compromises long-term efficacy of targeted cancer therapies.
- Resistance develops through non-genetic drug tolerance followed by genetic mutations.
- Drug tolerance in tumors correlates with treatment relapse and poor survival.
Purpose of the Study:
- To review recent studies on mitochondrial mechanisms in cancer therapy resistance.
- To emphasize the emerging concept of mitochondria-targeting triplet therapies.
- To discuss strategies for clinical translation of these therapies.
Main Methods:
- Review of recent scientific literature on cancer therapy resistance and mitochondria.
- Analysis of preclinical data on triplet therapies including mitochondria-targeting compounds.
- Discussion of challenges and strategies for clinical translation.
Main Results:
- Mitochondrial mechanisms play a critical role in cancer cell sensitivity to targeted therapies.
- Established cancer therapies can have surprising effects on mitochondria.
- Mitochondria-targeting triplet therapies demonstrate promising preclinical efficacy against drug tolerance.
Conclusions:
- Novel therapeutic strategies are needed to overcome cancer therapy tolerance.
- Triplet therapies including mitochondria-targeting agents offer a promising approach.
- Addressing clinical translation challenges is crucial for the success of these therapies.
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