Abstract
MAT2A catalyzes the conversion of methionine to SAM which is a critical methyl donor for methylation pathways critical to cell differentiation and survival.1 Preclinical evidence suggests that inhibition of this pathway may lead to synthetic lethality in 'methionine addicted' cancers. However, off target impacts on neural function, including myelination, have the potential to cause neuropathy.1
We present the case of a 63 year old Chinese female with de novo metastatic lung squamous cell carcinoma harbouring a MTAP deletion. After progression on first line chemotherapy (carboplatin/pemetrexed/atezolizumab/ bevacizumab) a clinical trial of a MAT2A inhibitor was commenced. Following 2 months of treatment the patient developed progressive and severe myalgia, neuropathic pain and non-length-dependent sensorimotor disturbance. A demyelinating sensorimotor neuropathy involving intermediate and proximal nerve segments, meeting EFNS/PNS demyelinating criteria was identified. Neural oedema, without enhancement, was found asymmetrically involving the lumbosacral plexus. Extensive investigation, including CSF analysis, identified no alternate aetiology. Symptoms resolved with analgesia and drug cessation. No recurrence occurred with rechallenge with dose reduction and concurrent high dose B12 and folate supplementation.
To our knowledge no case of MAT2A inhibitor associated neuropathy has been described in the literature. As novel anti-cancer therapies are discovered it remains important to ensure that potential toxicities, and their mechanisms, are understood to enable clinicians to identify ways of mitigating and treating these while maintaining anti-tumour effects.
Reference
Jiamin Guo, et al. Targeting the methionine-methionine adenosyl transferase 2AS-adenosyl methionine axis for cancer therapy. Curr Opin Oncol. 2022 Sep 1;34(5):546–551.
