Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status.
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 act with different mechanisms in NSCLCs, depending on EGFR/Ras mutational profile, and may be integrated with EGFR or MEK inhibitors for different cohorts of NSCLCs.
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Luigi
L
Formisano
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Valentina
V
D'Amato
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Alberto
A
Servetto
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Simona
S
Brillante
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Lucia
L
Raimondo
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Concetta
C
Di Mauro
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Roberta
R
Marciano
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Roberta Clara
RC
Orsini
DiSTABiF, Second University of Naples, Caserta, Italy.
Sandro
S
Cosconati
Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
Antonio
A
Randazzo
Department of Microbiology, Immunology & Cancer Biology, Cancer Center, University of Virginia Health System, Charlottesville, Virginia, USA.
Sarah J
SJ
Parsons
Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
Nunzia
N
Montuori
Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy.
Bianca Maria
BM
Veneziani
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Sabino
S
De Placido
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Roberta
R
Rosa
Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
Roberto
R
Bianco
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000494:pharmacology; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000068818:Cetuximab / Q000008:administration & dosage / Q000494:pharmacology; D000069439:Dasatinib / Q000008:administration & dosage / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D034622:RNA Interference; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019061:src-Family Kinases; D018631:ras Proteins; D000068818:Cetuximab; D000069439:Dasatinib
EGFR inhibitors; MEK inhibitors; NSCLC; Src; drug resistance