RT Journal Article
SR Electronic
T1 Concurrent Pemetrexed With EGFR-TKI Slows the Accumulation of <em>De Novo</em> Mutations During <em>In Vitro</em> Exposure
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 1323
OP 1335
DO 10.21873/anticanres.18032
VO 46
IS 3
A1 HAQUE, ESHAT F.
A1 TANINO, RYOSUKE
A1 OKIMOTO, TAMIO
A1 HOTTA, TAKAMASA
A1 OKUNO, TAKAE
A1 KONO, KENTO
A1 TSUBATA, YUKARI
A1 ISOBE, TAKESHI
YR 2026
UL http://ar.iiarjournals.org/content/46/3/1323.abstract
AB Background/Aim: Resistance to targeted therapy limits its efficacy in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Although concurrent administration of pemetrexed (PEM) and EGFR-tyrosine kinase inhibitors (TKIs) has yielded clinical benefits, it remains unclear whether concurrent PEM influences de novo mutations in the EGFR-TKI therapy. To address this gap, we aimed to compare the time to acquired resistance and accumulation of de novo tumor mutational burden (TMB) during in vitro exposure to osimertinib (OSI) and gefitinib (GEF), as well as their respective combinations with PEM.Materials and Methods: EGFR-mutated PC-9 cells were continuously exposed to EGFR-TKIs, alone or in combination with PEM, at equimolar concentrations. The drug concentration gradually increased to 1 and 3 μM for OSI and GEF, respectively. Whole-exome sequencing and quantitative PCR were performed to measure TMB and gene expression, respectively.Results: Concurrent PEM with either OSI or GEF extended the treatment duration compared to single EGFR-TKIs, decreased the de novo accumulated TMB per treatment time, and increased the expression of POLE2, POLQ, MLH1, BRCA1, BRCA2, RAD51, and FEN1 compared to that of single EGFR-TKIs.Conclusion: Concurrent PEM with EGFR-TKI treatment slowed TMB accumulation rate and resistance acquisition in EGFR-mutated NSCLC compared to single EGFR-TKIs in vitro.