In brief
- Immunohistochemistry showed MTAP loss in 42 of 243 NSCLC specimens (17%): 13% of early-stage and 20% of metastatic specimens.
- Among stage 4 tumours, MTAP loss was found in 24% of driver-positive and 14% of driver-negative cases (p=0.314).
- Primary tumour and lymph node staining agreed in 21 of 33 paired cases (64%).
- In 22 MTAP-deleted cell lines with EGFR, KRAS or ALK alterations, sensitivity to PRMT5 inhibitors varied and was independent of TKI exposure and SDMA expression.
- Combinations of a TKI and a PRMT5 inhibitor were more active than monotherapy in these cell lines.
Study at a glance
- Cohort: 243 NSCLC specimens from 240 patients
- Population: 132 early-stage and 111 metastatic specimens; 72% with driver alterations, 90% adenocarcinoma
- Method: MTAP expression by immunohistochemistry, including 33 specimens with paired lymph nodes
- Main finding: MTAP loss in 42 specimens (17%)
- Stage 4 subgroup: 24% of driver-positive vs 14% of driver-negative tumours (p=0.314)
- Laboratory work: 22 MTAP-deleted cell lines (9 EGFR-mutant, 7 KRAS-mutant, 6 ALK-rearranged)
- Not reported: the names of the PRMT5 inhibitors and TKIs tested; any animal or patient treatment data in the abstract
MTAP loss in one specimen in six, 13% early-stage and 20% metastatic
Staining was absent in 17 early-stage specimens and 22 metastatic specimens; the abstract does not assign the other three of the 42 specimens to either group, and gives no test of the early-stage versus metastatic difference. Current prevalence estimates rest on next-generation sequencing, which can underestimate copy losses, and this study used protein staining instead.
A driver alteration was present in 72% of patients and adenocarcinoma in 90%, a higher share of driver-positive disease than in an unselected NSCLC population.
A higher rate in stage 4 driver-positive tumours, without statistical significance
In stage 4 disease the comparison was 24% with a driver alteration against 14% without, with p=0.314. The abstract does not give the number of stage 4 tumours in each group, so the size of the subgroups behind these percentages cannot be judged from it.
The authors nonetheless use the 24% figure in their conclusion, stating that MTAP loss occurs in 24% of oncogene-driven tumours and that the findings support evaluation of PRMT5 inhibitors with TKIs in that group.
Lymph nodes did not always match the primary tumour
Lung and nodal staining agreed in 21 of the 33 paired cases (64%). In eight cases, decreased MTAP expression was seen only in the lymph node.
The abstract reports the nodal pattern without a breakdown by stage or driver status, and it does not say how the other paired cases differed.
PRMT5 inhibitors active in TKI-resistant cell lines, more so with a TKI
The laboratory work tested PRMT5 inhibitors alone and with TKIs in 22 MTAP-deleted NSCLC cell lines: nine EGFR-mutant, seven KRAS-mutant and six ALK-rearranged. Sensitivity varied between lines, and responses occurred in TKI-sensitive as well as TKI-resistant lines.
Expression of symmetric dimethylarginine (SDMA) did not predict which lines were sensitive to PRMT5 inhibition. Combinations of a TKI and a PRMT5 inhibitor had greater activity than monotherapy.
“These findings support evaluation of PRMT5 inhibitor + TKIs in oncogene-driven NSCLC.”Sakai et al., Clinical Cancer Research (2026)
All of the treatment evidence reported in the abstract comes from cell lines.
Sources
- Clinical Cancer Research. Prevalence and Actionability of MTAP Loss in Driver Oncogene-Positive and Oncogene-Negative Lung Cancer (2026-11-10). doi.org
Featuring Lung Summit faculty
This study was co-authored by Lung Summit faculty Zofia Piotrowska.
This article was produced independently by the Lung Summit editorial team, without industry funding or input.
