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ULK1's role in cancer progression and its emerging therapeutic potential

Jack D Webb1,2, Trevor G Shepherd1,2,3,4

  • 1The Mary & John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer Centre, London, ON, Canada.

Cancer Biology & Therapy
|June 17, 2026
PubMed

Insights

Macroautophagy (autophagy) is crucial for cellular stress adaptation. This review explores ULK1 kinase

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Pharmacology

Background:

  • Macroautophagy (autophagy) is a cellular degradation process essential for stress adaptation.
  • ULK1, a key kinase, initiates autophagy in response to nutrient and energy signals.
  • Limited research has directly investigated ULK1's role in cancer progression.

Purpose of the Study:

  • To review ULK1's function as a regulator of cancer progression.
  • To synthesize pan-cancer clinical and functional evidence on ULK1.
  • To discuss the evolving pharmacology of ULK1 modulation for cancer therapy.

Main Methods:

  • Literature review synthesizing functional data across numerous cancers.
  • Analysis of emerging evidence on ULK1's role in malignant behavior.
  • Review of advancements in ULK1/2 inhibitor development and clinical translation.

Main Results:

  • ULK1 influences cancer progression through both autophagy-dependent and -independent mechanisms.
  • ULK1 modulates key cancer hallmarks including mitochondrial quality, anoikis escape, invasion, and immune visibility.
  • New ULK1 inhibitors show improved potency and selectivity, with a first-in-class agent (DCC-3116) in clinical trials.

Conclusions:

  • ULK1 plays a dual role in cancer, promoting or restraining malignant behavior.
  • Targeted ULK1 inhibition is a promising therapeutic strategy in specific cancer contexts.
  • Understanding ULK1's complex roles is crucial for effective clinical translation.
Keywords:
ULK1autophagycancerinhibitorsmetastasisnon-canonicalpharmacology

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