2. Academic Validation
  3. Prevalence and Actionability of MTAP Loss in Oncogene-Driven Lung Cancer

Prevalence and Actionability of MTAP Loss in Oncogene-Driven Lung Cancer

  • bioRxiv. 2026 Jan 23:2026.01.21.700721. doi: 10.64898/2026.01.21.700721.
Takashi Sakai 1 2,  Zofia Piotrowska 1 2,  Charlotte I Wang 2 3,  Beow Y Yeap 1 2,  Rebecca S Heist 1 2,  Jessica J Lin 1 2,  Lauren E Highfield 1,  Jennifer L Petersen 1,  Mandeep Banwait 1,  Joyce Liang 1,  Manisha Madhavan 4,  Aaron N Hata 1 2,  Mari Mino-Kenudson 2 4,  Ibiayi Dagogo-Jack 1 2
Affiliations

Affiliations

  • 1 Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital.
  • 2 Harvard Medical School.
  • 3 Center for Integrated Diagnostics, Massachusetts General Hospital.
  • 4 Department of Pathology, Massachusetts General Hospital.
PMID: 41648424 DOI: 10.64898/2026.01.21.700721
Abstract

Background: Methylthioadenosine Phosphorylase (MTAP) loss co-occurs with actionable genomic alterations in non-small cell lung Cancer (NSCLC) and creates vulnerability to protein arginine methyltransferase 5 (PRMT5) inhibition. Estimates of prevalence of MTAP loss rely on next-generation Sequencing which can underestimate copy losses. Moreover, the activity of PRMT5 inhibitors in oncogene-driven NSCLC is not well established.

Methods: We assessed MTAP expression by immunohistochemistry (IHC) in 243 NSCLCs (n=132 early stage, n=111 metastatic), including 33 specimens with paired lymph nodes. Antiproliferative activity of PRMT5 Inhibitor monotherapy and in combination with tyrosine kinase inhibitors (TKIs) was evaluated in MTAP-deleted NSCLC cell lines harboring EGFR or KRAS mutations or ALK rearrangements.

Results: Among 243 NSCLC specimens from 240 patients (72% with driver alterations, 90% adenocarcinoma), MTAP loss was identified in 43 (18%) specimens from 40 (17%) patients, including 18 (14%) early-stage and 22 (20%) metastatic tumors. MTAP loss occurred in 24% of stage 4 driver-positive NSCLCs versus 14% of driver-negative tumors (p=0.314). Twenty (61%) lung-nodal pairs demonstrated concordance; eight cases only exhibited decreased MTAP expression in nodes. Variable sensitivity to PRMT5 inhibitors was observed in 22 MTAP-deleted NSCLC cell lines (9 EGFR-mutant, 7 KRAS-mutant, 6 ALK-rearranged), with responses seen in TKI-sensitive and TKI-resistant lines. SDMA (symmetric dimethylarginine) expression did not predict PRMT5 Inhibitor sensitivity. TKI + PRMT5 Inhibitor combos had greater activity than monotherapy.

Conclusions: MTAP loss occurs in 1-in-5 oncogene-driven metastatic NSCLCs. PRMT5 Inhibitor activity is independent of TKI exposure, driver alteration, and SDMA expression and enhanced by addition of TKI. These findings support clinical evaluation of PRMT5 Inhibitor + TKI combinations for advanced NSCLC.

Keywords

ALK; EGFR; KRAS; Lung cancer; MTAP.

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