Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR

Bell, Daphne W.; Gore, Ira; Okimoto, Ross A.; Godin-Heymann, Nadia; Sordella, Raffaella; Mulloy, Roseann; Sharma, Sreenath V.; Brannigan, Brian W.; Mohapatra, Gayatry; Settleman, Jeff; Haber, Daniel A.

doi:10.1038/ng1671

Cited by 468 publications

(355 citation statements)

References 15 publications

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“…The reported double mutations (13)(14)(15)(16)(17)(18) generally involve a common activating mutation such as L858R and a rare mutation such as T790M. Concomitant T790M and L858R mutations confer gefitinib resistance in NSCLC patients (17,18).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…70,[179][180][181] Clinically, patients with EGFR exon 20 mutations do not respond to gefitinib. 67 Moreover, the appearance of a secondary mutation in exon 20 (T790M) accounts for B50% of acquired drug resistance.…”

Section: Mechanisms Of Resistance To Egfr Targeted Therapymentioning

confidence: 99%

“…195 The mutation T790M, which is associated with B50% of acquired resistance, has also been linked to primary resistance, although infrequently (o5% of such cases) (Figure 2). 179 Approximately 10-25% of EGFR-mutant lung adenocarcinomas do not respond to an EGFR TKI. 15 In addition to the previously mentioned mutations, even rarer primary mutations, such as D761Y, G719C, and E709A mutations, have also been shown to be insensitive to EGFR TKIs, and even more so when co-occurring with other genetic alterations.…”

Section: Primary Resistance To Egfr Targeted Therapymentioning

confidence: 99%

“…182,208,243 This mutation confers a survival advantage to the tumor and is selected while the patient is receiving anti-EGFR TKI treatment. 82,179 This secondary mutation is quite prevalent, being found in up to 50% of EGFR-mutant tumors treated with first-generation EGFR TKIs. 182,208 Arcila et al 244 recently analyzed sensitizing EGFR mutations in 121 lung cancer patients, but only 104 (86%) cases were tested successfully.…”

Section: Acquired Resistance To Egfr Tkimentioning

confidence: 99%

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Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…1C and 2), an acquired secondary mutation that resulted in resistance to EGFR TKIs in about 50% of NSCLC patients, who initially responded to the therapy. 12-14 T790M mutation was also found to increase the activity of EGFR itself, 33 and some NSCLC patients who never received TKI treatments had spontaneous T790M mutation. 34 This could be explained by our finding that the direct binding of EPAS1 to T790M EGFR could significantly elevate MET levels ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells

Zhen

Liu

et al. 2015

Cancer Biology & Therapy

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Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; TKIs, tyrosine kinase inhibitors; EPAS1, endothelial PAS domain-containing protein 1; HIF)-1a., hypoxia-inducible factorMutations in epidermal growth factor receptor (EGFR) rendering it constitutively active is one of the major causes for metastatic non-small-cell lung cancer (NSCLC), and EGFR-targeted therapies utilizing tyrosine kinase inhibitors (TKIs) are often used clinically as the first-line treatment. But approximately half of NSCLC patients develop resistance to these therapies, where the MET proto-oncogene is amplified by EGFR through the hypoxia-inducible factor (HIF)-1a. Here we report that endothelial PAS domain-containing protein 1 (EPAS1), with 48% sequence identity to HIF-1a, specifically binds to TKI-resistant T790M EGFR, but not to wild-type EGFR, in NSCLC cell lines. Expression of EPAS1 enhances amplification of MET when simultaneously expressed with T790M EGFR but not with wild-type EGFR, and this enhancement is independent of ligand binding domain of EGFR. MET amplification requires EPAS1, since EPAS1 knockdown reduced MET levels. When NSCLC cells expressing T790M EGFR were treated with TKIs, reduced EPAS1 levels significantly enhanced the drug effect, whereas over-expression of EPAS1 increased the drug resistant effect. This EPAS1-dependent TKI-resistance was abolished by knocking-down MET, suggesting that EPAS1 does not cause TKIresistance itself but functions to bridge EGFR and MET interactions. Our findings suggest that EPAS1 is a key factor in the EGFR-MET crosstalk in conferring TKI-resistance in NSCLC cases, and could be used as a potential therapeutic target in TKI-resistant NSCLC patients.

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Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR

Cited by 468 publications

References 15 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

Molecular pathology of lung cancer: key to personalized medicine

Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells

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