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Nucleic Acid Therapeutics for "Undruggable" Cancer Targets: Mechanisms, Challenges, and Prospects

Feng Xu1, Ke Wang2, Kaizhong Lu1

  • 1Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 28, 2026
PubMed

Insights

Nucleic acid therapeutics offer a new way to target difficult cancer oncoproteins like Ras, MYC, and p53. These therapies work at the mRNA and genomic levels, overcoming limitations of traditional drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Key cancer oncoproteins (Ras, MYC, p53) are historically "undruggable" by conventional drugs.
  • Traditional drugs require specific structural domains, which these targets lack.
  • Precision oncology needs novel therapeutic strategies for these challenging targets.

Purpose of the Study:

  • To review nucleic acid therapeutics for "undruggable" cancer targets.
  • To examine mechanisms, translational progress, and challenges of nucleic acid modalities.
  • To highlight future directions for targeting intractable oncoproteins.

Main Methods:

  • Systematic review of nucleic acid therapeutics (ASOs, siRNAs, miRNAs, aptamers, mRNA vaccines).
  • Analysis of mechanisms: transcript degradation, translational inhibition, regulatory interference.
  • Critical evaluation of translational bottlenecks: delivery, safety, manufacturing.

Main Results:

  • Nucleic acid therapeutics bypass protein structure limitations by targeting mRNA and genomic levels.
  • Diverse modalities show promise against Ras, MYC, and p53.
  • Nanocarrier platforms are advancing delivery efficiency and safety.

Conclusions:

  • Nucleic acid therapeutics represent a paradigm shift in cancer treatment.
  • These therapies enable precise regulation of historically "undruggable" cancer targets.
  • Advances in technology and computational design will further enhance their potential.
Keywords:
MYCNucleic acid therapeuticsRasp53undruggable targets

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