Inhibition by erlotinib of primary lung adenocarcinoma at an early stage in male mice.
OBJECTIVE
Erlotinib, a small molecule inhibitor of the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR), increases survival of advanced non-small cell lung cancer patients who failed standard chemotherapy (Phase III study). We evaluated whether erlotinib is also effective at an early stage of primary lung tumorigenesis in a carcinogen-induced lung tumor model in mice.


METHODS
Sixteen weeks after carcinogen (urethane) injection, when small self-contained adenomas are evident, male and female A/J mice were treated IP with 10 mg/kg erlotinib or Captisol vehicle daily over 3.5 weeks (15 mice per group). The efficacy, metabolism and mechanism of action of erlotinib were evaluated.


RESULTS
Erlotinib reduced tumor burden in males by twofold compared to vehicle (12.7 +/- 1.2 vs 26.2 +/- 2.5 mg, respectively; p < 0.0001), while tumor burden in erlotinib-treated females slightly increased compared to vehicle by 21% (15.1 +/- 1.2 vs 11.9 +/- 0.9 mg, respectively; p < 0.05). Tumor multiplicity, in contrast, was unaffected by erlotinib. The levels of erlotinib that accumulated in plasma, lung tumor tissue and adjacent uninvolved (UI) lung were comparable in males and females. Males, however, accumulated more OSI-420, an active and pharmacologically equipotent metabolite of erlotinib, than females in plasma, lung tumors, and UI lung. In both genders, 80% of tumors contained Kras mutations at codon 61, but no EGFR mutations were detected. The cellular distribution and concentration of EGFR were also similar between genders. In control mice, however, phosphorylated EGFR (pEGFR) levels were nearly 2.5-fold higher in males compared to females in UI lungs and sevenfold higher in lung tumors. Further, erlotinib decreased the contents of pEGFR in UI lungs and lung tumors, particularly in males.


CONCLUSIONS
Adenomas from male mice in this early lung cancer model are responsive to erlotinib treatment, possibly because of a greater dependence of male tumor growth on the EGFR pathway compared to females. Importantly, these results indicate that small lung adenomas from male mice that utilize EGFR signaling but also harbor Kras mutations shrink in response to erlotinib, suggesting that erlotinib may be beneficial for some patients very early during lung cancer progression.
Zerbe
Laura K
LK
Department of Pharmaceutical Sciences, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Box C238, Denver, CO, 80262, USA.
Dwyer-Nield
Lori D
LD
Fritz
Jason M
JM
Redente
Elizabeth F
EF
Shroyer
Robert J
RJ
Conklin
Elizabeth
E
Kane
Shawn
S
Tucker
Chris
C
Eckhardt
S Gail
SG
Gustafson
Daniel L
DL
Iwata
Kenneth K
KK
Malkinson
Alvin M
AM
D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D007274:Injections, Intraperitoneal; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology*; D012737:Sex Factors
D000970:Antineoplastic Agents; C487471:OSI-420; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)