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AMPK promotes tolerance to Ras pathway inhibition by activating autophagy

Oncogene volume 35, pages 5295–5303 (2016)Cite this article

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Abstract

Targeted inhibitors of oncogenic Ras (rat sarcoma viral oncogene)-Raf signaling have shown great promise in the clinic, but resistance remains a major challenge: 30% of tumors with pathway mutations do not respond to targeted inhibitors, and of the 70% that do respond, all eventually develop resistance. Before cancer cells acquire resistance, they respond to initial drug treatment either by undergoing apoptosis ('addiction') or by surviving treatment albeit with reduced growth ('tolerance'). As these drug-tolerant cells serve as a reservoir from which resistant cells eventually emerge, inhibiting the pathways that confer tolerance could potentially delay or even prevent recurrence. Here, we show that melanomas and other cancers acquire tolerance to Ras-Raf pathway inhibitors by activating autophagy, which is mediated by the cellular energy sensor AMP-activated protein kinase (AMPK). Blocking this AMPK-mediated autophagy sensitizes drug-tolerant melanomas to Ras-Raf pathway inhibitors. Conversely, activating AMPK signaling and autophagy enables melanomas that would otherwise be addicted to the Ras-Raf pathway to instead tolerate pathway inhibition. These findings identify a key mechanism of tolerance to Ras-Raf pathway inhibitors and suggest that blocking either AMPK or autophagy in combination with these targeted inhibitors could increase tumor regression and decrease the likelihood of eventual recurrence.

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Abbreviations

BRAF:

v-Raf murine sarcoma viral oncogene homolog B

RAS:

rat sarcoma viral oncogene

AMPK:

AMP-activated protein kinase

AICAR:

5-aminoimidazole-4-carboxamide ribonucleotide

GFP:

green fluorescent protein

LC3B:

microtubule-associated protein 1 light chain 3 beta

CQ:

chloroquine

Baf:

bafilomycin

ATG:

autophagy-related protein

wt:

wild type

mut:

mutant

shRNA:

short hairpin RNA.

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Acknowledgements

We thank Dr Tyler Jacks for providing us with mouse KRASmut/p53−/− NSCLC line, the Whitehead flow cytometry facility, and Nicki Watson and Wendy Salmon at the Whitehead Keck Imaging Facility for microscopy services. We thank Dr David Pincus and Dr Luke Whitesell for critical reading of the manuscript. This research was supported by grants from the Ellison Foundation (PBG) and Melanoma Research Alliance (#311800; PBG), a Yale SPORE in Skin Cancer funded by the National Cancer Institute (#1 P50 CA121974; RH), and funds from the NSFGRFP (#1122374; ESS).

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Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA

    S Sanduja, Y Feng, R A Mathis, E S Sokol, F Reinhardt & P B Gupta

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    R A Mathis, E S Sokol & P B Gupta

  3. Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

    R Halaban

  4. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA

    P B Gupta

  5. Harvard Stem Cell Institute, Cambridge, MA, USA

    P B Gupta

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Correspondence to P B Gupta.

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Sanduja, S., Feng, Y., Mathis, R. et al. AMPK promotes tolerance to Ras pathway inhibition by activating autophagy. Oncogene 35, 5295–5303 (2016). https://doi.org/10.1038/onc.2016.70

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