Oncogenic RAS induces a distinctive form of non-canonical autophagy mediated by the P38-ULK1-PI4KB axis PMID: 40055523

ADC Targets in Oncology

2026-04-10

Oncogenic RAS induces a distinctive form of non-canonical autophagy mediated by the P38-ULK1-PI4KB axis

Cell Res. 2025 Mar 7. doi: 10.1038/s41422-025-01085-9.

Xiaojuan Wang ^# ¹ ² ³ ⁴ ⁵ , Shulin Li ^# ¹ ² ³ ⁴ , Shiyin Lin ^# ⁶ , Yaping Han ¹ ² ³ ⁴ , Tong Zhan ³ , Zhiying Huang ¹ ² ³ ⁴ , Juanjuan Wang ³ , Ying Li ³ , Haiteng Deng ³ ⁷ , Min Zhang ⁸ ⁹ , Du Feng ¹⁰ ¹¹ ¹² , Liang Ge ¹³ ¹⁴ ¹⁵ ¹⁶

Affiliations

1. State Key Laboratory of Membrane Biology, Beijing, China.
2. Tsinghua-Peking Center for Life Sciences, Beijing, China.
3. School of Life Sciences, Tsinghua University, Beijing, China.
4. Beijing Frontier Research Center for Biological Structure, Beijing, China.
5. School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
6. State Key Laboratory of Respiratory Disease, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
7. MOE Key Laboratory of Bioinformatics, Beijing, China.
8. State Key Laboratory of Membrane Biology, Beijing, China. [email protected].
9. School of Pharmaceutical Sciences, Tsinghua University, Beijing, China. [email protected].
10. State Key Laboratory of Respiratory Disease, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
11. Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
12. The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
13. State Key Laboratory of Membrane Biology, Beijing, China. [email protected].
14. Tsinghua-Peking Center for Life Sciences, Beijing, China. [email protected].
15. School of Life Sciences, Tsinghua University, Beijing, China. [email protected].
16. Beijing Frontier Research Center for Biological Structure, Beijing, China. [email protected].
# Contributed equally.

Abstract

Cancer cells with Ras mutations exhibit enhanced Autophagy, essential for their proliferation and survival, making it a potential target for therapeutic intervention. However, the regulatory differences between RAS-induced Autophagy and physiological Autophagy remain poorly understood, complicating the development of cancer-specific anti-autophagy treatments. In this study, we identified a form of non-canonical Autophagy induced by oncogenic KRAS expression, termed RAS-induced non-canonical Autophagy via ATG8ylation (RINCAA). RINCAA involves distinct autophagic factors compared to those in starvation-induced Autophagy and incorporates non-autophagic components, resulting in the formation of non-canonical autophagosomes with multivesicular/multilaminar structures labeled by ATG8 family proteins (e.g., LC3 and GABARAP). We have designated these structures as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A notable feature of RINCAA is the substitution of the class III PI3K in canonical Autophagy with PI4KB in RINCAA. We identified a regulatory P38-ULK1-PI4KB-WIPI2 signaling cascade governing this process, where ULK1 triggers PI4KB phosphorylation at S256 and T263, initiating PI4P production, ATG8ylation, and non-canonical Autophagy. Importantly, elevated PI4KB phosphorylation at S256 and T263 was observed in RAS-mutated Cancer cells and colorectal Cancer specimens. Inhibition of PI4KB S256 and T263 phosphorylation led to a reduction in RINCAA activity and tumor growth in both xenograft and KPC models of pancreatic Cancer, suggesting that targeting ULK1-mediated PI4KB phosphorylation could represent a promising therapeutic strategy for RAS-mutated cancers.