Related Experiment Video

Updated: Feb 7, 2026

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Prevalence and Actionability of MTAP Loss in Oncogene-Driven Lung Cancer

Takashi Sakai1,2, Zofia Piotrowska1,2, Charlotte I Wang2,3

  • 1Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital.

Biorxiv : the Preprint Server for Biology
|February 6, 2026
PubMed
Abstract

Insights

Methylthioadenosine phosphorylase (MTAP) loss is common in non-small cell lung cancer (NSCLC) and indicates vulnerability to PRMT5 inhibitors. Combining PRMT5 inhibitors with TKIs shows promise for treating advanced NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Methylthioadenosine phosphorylase (MTAP) loss is observed with actionable genomic alterations in non-small cell lung cancer (NSCLC).
  • MTAP loss creates a vulnerability to protein arginine methyltransferase 5 (PRMT5) inhibition.
  • Current estimates of MTAP loss prevalence may underestimate its occurrence, and PRMT5 inhibitor efficacy in oncogene-driven NSCLC requires further investigation.

Purpose of the Study:

  • To assess the prevalence of MTAP loss in NSCLC using immunohistochemistry (IHC).
  • To evaluate the antiproliferative activity of PRMT5 inhibitors in MTAP-deleted NSCLC cell lines with common driver alterations.
  • To determine the efficacy of combining PRMT5 inhibitors with tyrosine kinase inhibitors (TKIs).

Main Methods:

  • MTAP expression was assessed by IHC in 243 NSCLC specimens.
  • Antiproliferative activity of PRMT5 inhibitor monotherapy and combination therapy with TKIs was evaluated in 22 MTAP-deleted NSCLC cell lines harboring EGFR, KRAS, or ALK alterations.

Main Results:

  • MTAP loss was identified in 18% of NSCLC specimens, including 20% of metastatic tumors.
  • PRMT5 inhibitor sensitivity varied among MTAP-deleted NSCLC cell lines, irrespective of TKI sensitivity or specific driver alteration.
  • Combination therapy with TKIs demonstrated enhanced activity compared to PRMT5 inhibitor monotherapy.

Conclusions:

  • MTAP loss affects approximately 1 in 5 metastatic NSCLCs with oncogenic drivers.
  • PRMT5 inhibitor efficacy is independent of TKI exposure, driver alteration, and SDMA expression.
  • PRMT5 inhibitor and TKI combination therapy warrants clinical evaluation for advanced NSCLC.
Keywords:
ALKEGFRKRASLung cancerMTAP

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