Oncogenic Activity of Epidermal Growth Factor Receptor Kinase Mutant Alleles Is Enhanced by the T790M Drug Resistance Mutation

Godin-Heymann, Nadia; Bryant, Ianthe; Rivera, Miguel N.; Ulkus, Lindsey E.; Bell, Daphne W.; Riese, David J.; Settleman, Jeffrey; Haber, Daniel A.

doi:10.1158/0008-5472.can-06-4625

Cited by 131 publications

(110 citation statements)

References 41 publications

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“…2B). Such enhancement of EGFR phosphorylation and activity by T790M in double mutants has also been showed by other researchers (34,35). However, detailed clinical studies are necessary to ascertain whether the in vitro differences would translate into clinically observable differences in the patients' responses.…”

Section: Discussionsupporting

confidence: 66%

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Tam

Leung

Tin

et al. 2009

Molecular Cancer Therapeutics

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Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas, especially from nonsmoking women of Asian descent. We have previously shown EGFR mutations occur in >70% of lung adenocarcinoma from nonsmokers in our population with a complex mutational profile, including 13% of EGFR double mutations. In this study, we investigated the in vitro gefitinib response of four EGFR double mutants identified in untreated patients, including Q787R+L858R, E709A+G719C, T790M+L858R, and H870R+L858R. The phosphorylation profiles of EGFR and downstream effectors AKT, STAT3/5, and ERK1/2 were compared by immunoblot analyses among the single and double mutants transfected into H358 cells. Results showed that mutants responded to in vitro gefitinib treatment with different sensitivities. The G719C and L858R single mutants showed the highest gefitinib sensitivity compared with the corresponding coexisting single mutants E709A, Q787R, H870R, and T790M. The double mutants E709A+G719C, Q787R+L858R, and H870R+L858R showed attenuated responses to gefitinib in the EGFR and downstream effector phosphorylation profiles compared with G719C or L858R alone. T790M+L858R showed strong resistance to gefitinib. Clinically, the patient whose tumor contained H870R+L858R showed tumor stabilization by 250 mg oral gefitinib daily but cerebral metastasis developed 6 months later. Correlation with the in vitro phosphorylation profile of H870R +L858R suggested that treatment failure was probably due to inadequate suppression of EGFR signaling by the drug level attainable in the cerebrospinal fluid at the given oral dosage. Overall, the findings suggested that rare types of EGFR substitution mutations could confer relative gefitinib resistance when combined with the common activating mutants. [Mol Cancer Ther

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Section: Discussionsupporting

confidence: 66%

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Tam

Leung

Tin

et al. 2009

Molecular Cancer Therapeutics

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“…Of the four mutant EGFR cell lines we examined, all contain additional genetic alterations that boost EGFR signaling, and some of these changes also confer resistance to EGFRIs. For example, both HCC827 and H3255 exhibit amplification at the EGFR locus, dramatically enhancing EGFR signaling, whereas H1975 carries the T790M mutation that, when combined in cis with L858R or del746-750 mutations, boosts EGFR signaling (26). The T790M mutation also confers resistance to gefitinib by blocking drug binding (SI Fig.…”

Section: Discussionmentioning

confidence: 99%

Signaling networks assembled by oncogenic EGFR and c-Met

Guo

Villén

Kornhauser

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

470

427

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“…The double mutations not only confer resistance to gefitinib/erlotinib but also result in markedly enhanced catalytic kinase and oncogenic activity (Mulloy et al, 2007). Emerging evidence suggests that the T790M 'gatekeeper' mutation may exist in lung tumours before EGFR-TKI therapeutic selection (Bell et al, 2005;Godin-Heymann et al, 2007), partly due to its enhanced oncogenicity, and accounts for the adverse clinical course and outcome in gefitinib/erlotinib-resistance lung cancers after a course of rapid TKI selection. Interestingly, we found that H1975 cells co-express EGFR and MET at high level, although without any MET genomic amplification, and were capable of serum-independent constitutive MET activation.…”

Section: Discussionmentioning

confidence: 99%

Dual MET–EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer

et al. 2008

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Despite clinical approval of erlotinib, most advanced lung cancer patients are primary non-responders. Initial responders invariably develop secondary resistance, which can be accounted for by T790M-EGFR mutation in half of the relapses. We show that MET is highly expressed in lung cancer, often concomitantly with epidermal growth factor receptor (EGFR), including H1975 cell line. The erlotinib-resistant lung cancer cell line H1975, which expresses L858R/T790M-EGFR in-cis, was used to test for the effect of MET inhibition using the small molecule inhibitor SU11274. H1975 cells express wild-type MET, without genomic amplification (CNV ¼ 1.1). At 2 mM, SU11274 had significant in vitro pro-apoptotic effect in H1975 cells, 3.9-fold (P ¼ 0.0015) higher than erlotinib, but had no effect on the MET and EGFR-negative H520 cells. In vivo, SU11274 also induced significant tumour cytoreduction in H1975 murine xenografts in our bioluminescence molecular imaging assay. Using small-animal microPET/MRI, SU11274 treatment was found to induce an early tumour metabolic response in H1975 tumour xenografts. MET and EGFR pathways were found to exhibit collaborative signalling with receptor cross-activation, which had different patterns between wild type (A549) and L858R/ T790M-EGFR (H1975). SU11274 plus erlotinib/CL-387,785 potentiated MET inhibition of downstream cell proliferative survival signalling. Knockdown studies in H1975 cells using siRNA against MET alone, EGFR alone, or both, confirmed the enhanced downstream inhibition with dual MET -EGFR signal path inhibition. Finally, in our time-lapse video-microscopy and in vivo multimodal molecular imaging studies, dual SU11274-erlotinib concurrent treatment effectively inhibited H1975 cells with enhanced abrogation of cytoskeletal functions and complete regression of the xenograft growth. Together, our results suggest that MET-based targeted inhibition using small-molecule MET inhibitor can be a potential treatment strategy for T790M-EGFR-mediated erlotinib-resistant non-small-cell lung cancer. Furthermore, optimised inhibition may be further achieved with MET inhibition in combination with erlotinib or an irreversible EGFR-TKI.

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Oncogenic Activity of Epidermal Growth Factor Receptor Kinase Mutant Alleles Is Enhanced by the T790M Drug Resistance Mutation

Cited by 131 publications

References 41 publications

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Signaling networks assembled by oncogenic EGFR and c-Met

Dual MET–EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer

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