2006;66:5542-5548. Cancer Res
Lanxi Song, Mark Morris, Tapan Bagui, et al.
Receptor Signaling for Survival
Lung Cancer Cells Dependent on Epidermal Growth Factor
Dasatinib (BMS-354825) Selectively Induces Apoptosis in
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Our results agree with recent studies, showing dasatinib-induced
apoptosis in head and neck cancer cells, another EGFR-dependent
tumor type (18). More work is required to understand how
dasatinib results in apoptosis in gefitinib-sensitive mutant EGFR
lung cancer cells. In addition to Src proteins, dasatinib has been
shown to bind other tyrosine kinase proteins, including EGFR, and,
in conjunction with our data, suggests that EGFR may be a direct
target of dasatinib or an indirect target secondary to Src inhibition
(7, 8, 11). In addition, Src signaling can regulate the PI3K/PTEN/
Akt axis through multiple mechanisms, including tyrosine phos-
phorylation of the regulatory p85 subunit of PI3K, tyrosine
phosphorylation of PTEN that results in compromised function
of PTEN, and modification of EGFR function through direct
phosphorylation of key tyrosine residues (7, 16). Despite ample
evidence that Src proteins can directly phosphorylate STAT3, only
in H3255 cells we observed clear inhibition of pSTAT3 with
dasatinib, and it is not clear if this is a direct effect on Src
inhibition or rather through modification of EGFR function (9).
Nonetheless, our results suggest that Src is not responsible for
high levels of activated STAT3 seen in cells with EGFR mutation.
It will be interesting to see if other Src tyrosine kinase inhibitors
(TKI) produce similar effects on lung cancer cells with activating
mutations in EGFR.
It will be important to examine the effect of dasatinib in
additional cells with acquired resistance to EGFR-TKI. Despite
dramatic responses in the subset of lung cancer patients with
EGFR dependence, the tumor cells ultimately acquire resistance to
EGFR-TKI therapy through either additional mutations in EGFR or
other mechanisms (19). Multiple inhibitors may be necessary to
overcome acquired resistance to TKIs in BCR-ABL-dependent
leukemia, and a similar paradigm may exist in the treatment of
EGFR-dependent lung cancer (20). Thus, combined attack on
EGFR-dependent survival pathways by multiple nonoverlapping
agents may be necessary to cure this subset of patients by avoiding
the development of resistant clones. Although speculative,
dasatinib added to EGFR-TKI may help suppress development of
resistant clones, but this obviously requires further testing. We
found no apoptotic effect of dasatinib on H1975 cells with the
T790M mutation, but this mechanism of resistance may be rare,
and further evaluation in other cell lines that have acquired
resistance to EGFR-TKI is indicated.
Dasatinib may have advantages over EGFR inhibitors in tumors
that are not dependent on EGFR for survival through promoting
tumor cell dormancy through cell cycle arrest and inhibition of
tumor cell invasion. This is important because the majority of
patients with advanced lung cancer do not have EGFR mutation.
Because Src signaling is implicated in oncogenic processes, such as
cell invasion, metastasis, and angiogenesis, these compounds could
have additional in vivo effects beyond the effects seen in these cell
culture models (6). Dasatinib is in early stages of clinical
development in patients with solid tumors, and it remains unclear
if patients can achieve dasatinib levels used in our studies that
induce apoptosis, cell cycle arrest, and inhibition of invasion. A
priori determination of lung cancers dependent on EGFR for
growth and/or survival may identify patient subsets that derive the
maximum benefit from dasatinib, and combination therapy with
EGFR inhibitors should be considered. Further work in both animal
models and clinical trials is indicated to validate this hypothesis.
Received 12/28/2005; revised 3/28/2006; accepted 4/10/2006.
Grant support: Joan’s Legacy Foundation and the LUNGevity Foundation
(E.B. Haura); NIH grants CA55652 and CA82533 (R. Jove); H. Lee Moffitt Cancer Center
Core, and Flow Cytometry Core at H. Lee Moffitt Cancer Center and Research Institute.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Dr. William Pao (Memorial Sloan-Kettering, New York, NY) for providing
EGFR plasmids, Dr. Pasi Janne for providing H3255 cells, Dr. Jon Kurie for providing
HCC827 cells, Dr. Matthew Lazzara for providing PC9 cells, and Vicki Lamm for
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