Translational reprogramming marks adaptation to asparagine restriction in cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Amino acid restriction is a promising cancer therapy, but metabolic adaptations hinder its efficacy.
• Understanding cellular survival mechanisms under nutrient stress is crucial for improving cancer treatments.

Purpose of the Study:

• To investigate the role of translational reprogramming in cancer cell survival during asparagine restriction.
• To identify signaling pathways involved in adaptation to asparagine deprivation.
• To evaluate the therapeutic potential of targeting these adaptive mechanisms.

Main Methods:

• Utilized melanoma and pancreatic cancer cell lines.
• Analyzed receptor tyrosine kinase-MAPK signaling pathway activation.
• Investigated the mammalian target of rapamycin complex 1 (mTORC1) and its downstream effectors, MAPK-interacting kinase 1 (MNK1) and eukaryotic translation initiation factor 4E (eIF4E).
• Assessed the translation of activating transcription factor 4 (ATF4) mRNA and the expression of its target, asparagine synthetase (ASNS).
• Evaluated the effect of MAPK inhibition on tumor growth in preclinical models.
• Correlated ASNS expression with response to MAPK inhibitors in melanoma patients.

Main Results:

• Asparagine limitation activates MAPK signaling through an mTORC1-dependent pathway, increasing MNK1 and eIF4E.
• This leads to enhanced translation of ATF4 mRNA, upregulating ASNS expression.
• MAPK inhibition reduces ATF4 translation and ASNS expression, sensitizing cancer cells to asparagine restriction.
• MAPK inhibition combined with asparagine restriction significantly inhibited tumor growth.
• Low ASNS expression predicts response to MAPK inhibitors in melanoma patients.

Conclusions:

• Identified a novel adaptive axis involving translational reprogramming and MAPK signaling in asparagine-restricted cancer cells.
• Demonstrated that targeting this axis, particularly with MAPK inhibitors, can overcome resistance to asparagine restriction.
• These findings provide a strong rationale for combining MAPK inhibitors with asparagine restriction strategies in clinical settings for cancer therapy.