Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors.
Targeted cancer therapies impede cancer cell growth by inhibiting the function of activated oncogene products. Patients with non-small cell lung cancer and somatic mutations of EGFR can have a dramatic response to treatment with erlotinib and gefitinib; different somatic mutations are associated with different times to progression and survival. In this study, the relative and absolute potencies of two distinct EGFR tyrosine kinase inhibitors, erlotinib and an investigational irreversible inhibitor, HKI-272, were found to vary significantly in a panel of Ba/F3 cells transformed by representative EGFR somatic mutations. HKI-272 more potently inhibited the primary exon 20 insertion mutants, the secondary erlotinib-resistance mutants including T790M and many erlotinib-sensitive mutants including L858R. In contrast, erlotinib is a more potent inhibitor of the major exon 19 deletion mutants than is HKI-272. Analyses of EGFR autophosphorylation patterns confirmed the mutation-specific variation in relative potency of these tyrosine kinase inhibitors. Our finding that distinct EGFR inhibitors are more effective in vitro for different mutant forms of the protein suggests that tyrosine kinase inhibitor treatment could be tailored to specific EGFR mutations. More broadly, these results imply that the development and deployment of targeted therapies should focus on inhibition of specific cancer-causing mutations, not only on the mutated target.
Yuza
Yuki
Y
Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Glatt
Karen A
KA
Jiang
Jingrui
J
Greulich
Heidi
H
Minami
Yuko
Y
Woo
Michele S
MS
Shimamura
Takeshi
T
Shapiro
Geoffrey
G
Lee
Jeffrey C
JC
Ji
Hongbin
H
Feng
Whei
W
Chen
Tzu-Hsiu
TH
Yanagisawa
Haruhiko
H
Wong
Kwok-Kin
KK
Meyerson
Matthew
M
D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry; D010766:Phosphorylation; D017354:Point Mutation; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012190:Retroviridae / Q000235:genetics; D017384:Sequence Deletion
D017931:DNA Primers; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C487932:neratinib