Modulating undruggable targets to overcome cancer therapy resistance
Catherine Passirani1, Anne Vessières2, Giuseppe La Regina3
1Micro et Nanomédecines Translationnelles, MINT, UNIV Angers, UMR INSERM 1066, UMR CNRS 6021, SFR ICAT, 49000, Angers, France.
Abstract:
Many cancer patients frequently fail to respond to anti-cancer treatment due to therapy resistance which is the major obstacle towards curative cancer treatment. Therefore, identification of the molecular mechanisms underlying resistance is of paramount clinical and economic importance. The advent of targeted therapies based on a molecular understanding of cancer could serve as a model for strategies to overcome drug resistance. Accordingly, the identification and validation of proteins critically involved in resistance mechanisms represent a path towards innovative therapeutic strategies to improve the clinical outcome of cancer patients. In this review, we discuss emerging targets, small molecule therapeutics and drug delivery strategies to overcome therapy resistance. We focus on rational treatment strategies based on transcription factors, pseudokinases, nuclear export receptors and immunogenic cell death strategy. Historically, unliganded transcription factors and pseudokinases were considered undruggable while blocking the nuclear export e.g., through inhibition of the nuclear export receptor CRM1 was predicted as highly toxic. Recent success inhibiting Gli-1, HIF-1α, HIF-2α and reactivating the tumor suppressor transcription factors p53 and FOXO illustrates the feasibility and power of this targeting approach. Similarly, progress has been made in modulating the activity of pseudokinase proteins implicated in therapy resistance including members of the Tribbles protein family. On the other hand, the recent clinical approval of Selinexor, a specific inhibitor of CRM-1, a protein that mediates the transport of cargos with leucine-rich nuclear export signals and known to be a driver of drug resistance, represents the proof-of-concept for inhibiting the nuclear export as a feasible strategy to overcome therapy resistance. The ever-growing capacity to target resistance mechanisms with judiciously selected small molecules, some of which are being formulated within smart nanoparticles, will pave the way towards the improvement of the clinical outcome and realize the full potential of targeted therapies and immunotherapies.
Insights
Overcoming cancer therapy resistance is crucial for effective treatment. New strategies target transcription factors, pseudokinases, and nuclear export, offering hope for improved patient outcomes with targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Therapy resistance is a major challenge in cancer treatment, hindering curative outcomes.
- Understanding the molecular basis of resistance is vital for developing effective strategies.
- Targeted therapies offer a promising avenue, but overcoming resistance remains a key obstacle.
Purpose of the Study:
- To review emerging molecular targets and therapeutic strategies for overcoming cancer therapy resistance.
- To highlight novel approaches including transcription factor modulation, pseudokinase inhibition, and nuclear export blockade.
- To discuss the potential of small molecule therapeutics and advanced drug delivery systems.
Main Methods:
- Review of current literature on molecular mechanisms of cancer therapy resistance.
- Analysis of emerging therapeutic targets such as transcription factors (Gli-1, HIF-1α, HIF-2α, p53, FOXO), pseudokinases (Tribbles family), and nuclear export receptors (CRM1).
- Discussion of small molecule inhibitors and drug delivery strategies, including nanoparticle formulations.
Main Results:
- Historically 'undruggable' targets like transcription factors and pseudokinases are now being successfully targeted.
- Inhibition of CRM1, a nuclear export receptor, has proven effective in overcoming drug resistance, as demonstrated by Selinexor's approval.
- Targeting resistance mechanisms with small molecules and advanced delivery systems shows potential for improving clinical outcomes.
Conclusions:
- Targeting specific molecular pathways involved in resistance, such as transcription factors and nuclear export, is a feasible and powerful strategy.
- The development of novel small molecule therapeutics and smart drug delivery systems is crucial for realizing the full potential of targeted therapies and immunotherapies.
- These advancements offer a path towards improved clinical outcomes for cancer patients facing therapy resistance.
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