Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status

Oncotarget
Luigi FormisanoRoberto Bianco

Abstract

Resistance to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, often related to Ras or secondary EGFR mutations, is a relevant clinical issue in Non-Small Cell Lung Cancer (NSCLC). Although Src TK has been involved in such resistance, clinical development of its inhibitors has been so far limited. To better define the molecular targets of the Src TKIs saracatinib, dasatinib and bosutinib, we used a variety of in vitro/in vivo studies. Kinase assays supported by docking analysis demonstrated that all the compounds directly inhibit EGFR TK variants. However, in live cells only saracatinib efficiently reduced EGFR activation, while dasatinib was the most effective agent in inhibiting Src TK. Consistently, a pronounced anti-proliferative effect was achieved with saracatinib, in EGFR mutant cells, or with dasatinib, in wt EGFR/Ras mutant cells, poorly dependent on EGFR and erlotinib-resistant. We then identified the most effective drug combinations to overcome resistance to EGFR inhibitors, both in vitro and in nude mice: in T790M EGFR erlotinib-resistant cells, saracatinib with the anti-EGFR mAb cetuximab; in Ras mutant erlotinib-resistant models, dasatinib with the MEK inhibitor selumetinib. Src inhibitors may a...Continue Reading

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Citations

Jun 24, 2018·International Journal of Molecular Sciences·Carmen SegrellesCorina Lorz
Jul 12, 2017·Molecular and Cellular Biology·Maho TakahashiPhilip J S Stork
May 8, 2018·Cancers·Federica Lo SardoGiovanni Blandino
Mar 14, 2021·Genomics, Proteomics & Bioinformatics·Xujun WangHui Lu
Mar 20, 2020·Cell Systems·Alexander G GogliaJared E Toettcher
Jun 12, 2018·Analytical Chemistry·Sang-Yun LeeDong Woo Lee

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BETA
ELISA
transfection
xenografts
X-ray
xenograft

Software Mentioned

UCSF Chimera
BMDP
BMDP New System
PathScan
Calcusyn
Sigma Plot
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