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  3. Translational reprogramming marks adaptation to asparagine restriction in cancer

Translational reprogramming marks adaptation to asparagine restriction in cancer

  • Nat Cell Biol. 2019 Dec;21(12):1590-1603. doi: 10.1038/s41556-019-0415-1.
Gaurav Pathria 1,  Joo Sang Lee # 2 3,  Erez Hasnis # 4,  Kristofferson Tandoc 5,  David A Scott 4,  Sachin Verma 4,  Yongmei Feng 4,  Lionel Larue 6 7 8,  Avinash D Sahu 9,  Ivan Topisirovic 3,  Eytan Ruppin 2,  Ze'ev A Ronai 10
Affiliations

Affiliations

  • 1 Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. gauravpathria@gmail.com.
  • 2 Cancer Data Science Lab (CDSL), National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
  • 3 Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
  • 4 Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 5 Gerald Bronfman Department of Oncology, Lady Davis Institute, SMBD Jewish General Hospital, and Departments of Experimental Medicine and Biochemistry, McGill University, Montreal, Quebec, Canada.
  • 6 Normal and Pathological Development of Melanocytes, Institut Curie, PSL Research University, INSERM U1021, Orsay, France.
  • 7 Universitê Paris-Sud and Université Paris-Saclay, CNRS UMR 3347, Orsay, France.
  • 8 Equipe Labellisée Ligue Contre le Cancer, Orsay, France.
  • 9 Harvard School of Public Health and Massachusetts General Hospital, Boston, MA, USA.
  • 10 Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. zeev@ronailab.net.
  • # Contributed equally.
PMID: 31740775 DOI: 10.1038/s41556-019-0415-1
Abstract

While amino acid restriction remains an attractive strategy for Cancer therapy, metabolic adaptations limit its effectiveness. Here we demonstrate a role of translational reprogramming in the survival of asparagine-restricted Cancer cells. Asparagine limitation in melanoma and pancreatic Cancer cells activates receptor tyrosine kinase-MAPK signalling as part of a feedforward mechanism involving mammalian target of rapamycin complex 1 (mTORC1)-dependent increase in MAPK-interacting kinase 1 (MNK1) and eukaryotic translation initiation factor 4E (eIF4E), resulting in enhanced translation of activating transcription factor 4 (ATF4) mRNA. MAPK inhibition attenuates translational induction of ATF4 and the expression of its target asparagine synthetase (ASNS), sensitizing melanoma and pancreatic tumours to asparagine restriction, reflected in inhibition of their growth. Correspondingly, low ASNS expression is among the top predictors of response to inhibitors of MAPK signalling in patients with melanoma and is associated with favourable prognosis when combined with low MAPK signalling activity. These studies reveal an axis of adaptation to asparagine deprivation and present a rationale for clinical evaluation of MAPK inhibitors in combination with asparagine restriction approaches.

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