Thoracic cancer
SRC Activation Drives Acquired Pemetrexed Resistance in Non-Small Cell Lung Cancer and Is Targetable by Dasatinib
By Seo J, Kim KJ, Kim SH and 17 others.
Abstract
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.