ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells.

Schläfli, Anna M; Tokarchuk, Igor; Parejo, Sarah; Jutzi, Susanne; Berezowska, Sabina; Engedal, Nikolai; Tschan, Mario P. (2021). ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells. Scientific reports, 11(1), p. 9011. Springer Nature 10.1038/s41598-021-87966-6

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ALK inhibitors effectively target EML4-ALK positive non-small cell lung cancer, but their effects are hampered by treatment resistance. In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted therapies on autophagic activity previously have been assessed by surrogate marker proteins such as LC3B, we here thoroughly examined effects on functional autophagic activity, i.e. on the sequestration and degradation of autophagic cargo, in addition to autophagic markers. Interestingly, the ALK inhibitor Ceritinib decreased mTOR activity and increased GFP-WIPI1 dot formation in H3122 and H2228 EML4-ALK+ lung cancer cells, suggesting autophagy activation. Moreover, an mCherry-EGFP-LC3B based assay indicated elevated LC3B carrier flux upon ALK inhibition. In accordance, autophagic cargo sequestration and long-lived protein degradation significantly increased upon ALK inhibition. Intriguingly, autophagic cargo flux was dependent on VPS34 and ULK1, but not LC3B. Co-treating H3122 cells with Ceritinib and a VPS34 inhibitor or Bafilomycin A1 resulted in reduced cell numbers. Moreover, VPS34 inhibition reduced clonogenic recovery of Ceritinib-treated cells. In summary, our results indicate that ALK inhibition triggers LC3B-independent macroautophagic flux in EML4-ALK+ cells to support cancer cell survival and clonogenic growth.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Tokarchuk, Igor; Berezowska, Sabina Anna and Tschan, Mario

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2045-2322

Publisher:

Springer Nature

Language:

English

Submitter:

Andrea Stettler

Date Deposited:

29 Apr 2021 11:41

Last Modified:

02 May 2021 03:07

Publisher DOI:

10.1038/s41598-021-87966-6

PubMed ID:

33907223

BORIS DOI:

10.48350/156130

URI:

https://boris.unibe.ch/id/eprint/156130

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