Thoracic cancer · 2026
SRC Activation Drives Acquired Pemetrexed Resistance in Non-Small Cell Lung Cancer and Is Targetable by Dasatinib.
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Seo Jeongmin, Kim Kui-Jin, Kim Se Hyun, Sung Ji Hea, Hwang Sung-Hyun, Park Woochan, Kang Minsu, Jung Eun Hee, Kim Sang-A, Suh Koung Jin, Lee Ji Yun, Kim Ji-Won, Lee Jeong-Ok, Kim Jin Won, Kim Yu Jung, Lee Keun-Wook, Kim Jee Hyun, Bang Soo-Mi, Kwon Ji-Hyun, Lee Jong Seok
Аннотация
PURPOSE: Pemetrexed, a standard antifolate chemotherapy for non-squamous non-small cell lung cancer (NSCLC), is often limited by acquired resistance. We investigated whether SRC kinase mediates pemetrexed resistance and whether SRC inhibition can suppress survival signaling in pemetrexed-resistant NSCLC cells.
METHODS: Pemetrexed-resistant cell lines (PC9 R, NCI-H460 R, and NCI-H3122 R) were generated through chronic pemetrexed exposure. Protein phosphorylation profiling and Western blotting identified key signaling alterations. SRC was abrogated using transient and doxycycline-inducible CRISPR/Cas9 systems, and reciprocal siRNA knockdown of SRC and thymidylate synthase (TS) was performed. Three SRC inhibitors-dasatinib, bosutinib, and saracatinib-were assessed using cell viability, colony formation, apoptosis, and cell cycle assays.
RESULTS: All pemetrexed-resistant cell lines demonstrated elevated phosphorylated SRC (p-SRC Y416) and enhanced downstream signaling. SRC knockout reduced p-SRC Y416, p-STAT3, and p-FAK, while increasing markers of DNA damage (γ-H2AX) and apoptosis (cleaved caspase-3), impairing cell viability and clonogenicity. SRC knockdown reduced TS expression in two resistant models, whereas TS knockdown did not suppress p-SRC Y416. Among SRC inhibitors, dasatinib showed the most potent, dose-dependent suppression of SRC signaling. Dasatinib also induced G0/G1 arrest, DNA damage, and apoptosis, thereby reducing colony formation.
CONCLUSION: SRC activation is a critical mechanism of acquired pemetrexed resistance in NSCLC and may contribute to resistance through TS-associated survival signaling. SRC inhibition, particularly with dasatinib, disrupts pro-survival pathways and promotes DNA damage-mediated cell death in pemetrexed-resistant cells. These findings support further investigation of SRC inhibitors, alone or with pemetrexed, as a biomarker-guided therapeutic strategy for SRC-activated pemetrexed-resistant NSCLC.
METHODS: Pemetrexed-resistant cell lines (PC9 R, NCI-H460 R, and NCI-H3122 R) were generated through chronic pemetrexed exposure. Protein phosphorylation profiling and Western blotting identified key signaling alterations. SRC was abrogated using transient and doxycycline-inducible CRISPR/Cas9 systems, and reciprocal siRNA knockdown of SRC and thymidylate synthase (TS) was performed. Three SRC inhibitors-dasatinib, bosutinib, and saracatinib-were assessed using cell viability, colony formation, apoptosis, and cell cycle assays.
RESULTS: All pemetrexed-resistant cell lines demonstrated elevated phosphorylated SRC (p-SRC Y416) and enhanced downstream signaling. SRC knockout reduced p-SRC Y416, p-STAT3, and p-FAK, while increasing markers of DNA damage (γ-H2AX) and apoptosis (cleaved caspase-3), impairing cell viability and clonogenicity. SRC knockdown reduced TS expression in two resistant models, whereas TS knockdown did not suppress p-SRC Y416. Among SRC inhibitors, dasatinib showed the most potent, dose-dependent suppression of SRC signaling. Dasatinib also induced G0/G1 arrest, DNA damage, and apoptosis, thereby reducing colony formation.
CONCLUSION: SRC activation is a critical mechanism of acquired pemetrexed resistance in NSCLC and may contribute to resistance through TS-associated survival signaling. SRC inhibition, particularly with dasatinib, disrupts pro-survival pathways and promotes DNA damage-mediated cell death in pemetrexed-resistant cells. These findings support further investigation of SRC inhibitors, alone or with pemetrexed, as a biomarker-guided therapeutic strategy for SRC-activated pemetrexed-resistant NSCLC.