Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation.

Sos, Martin L.; Rode, Haridas B.; Heynck, Stefanie; Peifer, Martin; Fischer, Florian; Klüter, Sabine; Pawar, Vijaykumar G.; Reuter, Cecile; Heuckmann, Johannes M.; Weiss, Jonathan; Ruddigkeit, Lars; Rabiller, Matthias; Koker, Mirjam; Simard, Jeffrey R.; Getlik, Matthäus; Yuza, Yuki; Chen, Tzu-Hsiu; Greulich, Heidi; Thomas, Roman K.; Rauh, Daniel

doi:10.1158/0008-5472.can-09-3106

Cited by 220Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchComputational Drug Discovery Methods

Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation.

Sos, Martin L., Rode, Haridas B., Heynck, Stefanie, Peifer, Martin, Fischer, Florian, Klüter, Sabine, Pawar, Vijaykumar G., Reuter, Cecile +12 more·2010·Cancer Research

DOI 10.1158/0008-5472.can-09-3106

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Abstract

Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired resistance by the T790M resistance mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors. A focused library of irreversible as well as structurally corresponding reversible EGFR-inhibitors was synthesized for chemogenomic profiling involving over 79 genetically defined NSCLC and 19 EGFR-dependent cell lines. Overall, our results show that the growth-inhibitory potency of all irreversible inhibitors against the EGFR(T790M) resistance mutation was limited by reduced target inhibition, linked to decreased binding velocity to the mutant kinase. Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis. Our findings offer a mechanistic explanation for the limited efficacy of irreversible EGFR inhibitors in EGFR(T790M) gatekeeper-mutant tumors, and they prompt combination treatment strategies involving inhibitors that target signaling downstream of the EGFR.

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T790M makes EGFR refractory to reversible TKIs through steric hindrance and increased ATP affinity.
“The T790M mutation is believed to render the receptor refractory to inhibition by these reversible EGFR TKIs through exerting effects on both steric hindrance (22) and increased ATP affinity (23).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [22]

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Background
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21 High sensitivity detection of epidermal growth factor receptor (EGFR) T790M mutants in non-small-cell lung cancer
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9017 POSTER DISCUSSION Initial Detection of the Double Epidermal Growth Factor Receptor (EGFR) Mutation (L858R or Deletion in Exon 19 [del 19] Plus T790M) in Non-Small-Cell Lung Cancer (NSCLC) Patients (p) With Brain Metastases (mets) and the Influence of First-Line Chemotherapy on Outcome to Erlotinib
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Authors: Sos, M. L., Rode, H. B., Heynck, S., Peifer, M., Fischer, F., Klüter, S., Pawar, V. G., Reuter, C., Heuckmann, J. M., Weiss, J., Ruddigkeit, L., Rabiller, M., Koker, M., Simard, J. R., Getlik, M., Yuza, Y., Chen, T.-H., Greulich, H., Thomas, R. K., & Rauh, D.
Affiliations: Broad Institute (US)
Corresponding author: Rauh, Daniel
ORCID: Sos, Martin L.
Rode, Haridas B.
Peifer, Martin
Heuckmann, Johannes M.
Weiss, Jonathan
Simard, Jeffrey R.
Yuza, Yuki
Greulich, Heidi
Thomas, Roman K.
Rauh, Daniel
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2010-01-31
Volume: 70
Issue: 3
Pages: 868-874
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-09-3106
OpenAlex: W2138536086
Cited by: 220
References: 20
Citations by year: 2026: 3 · 2025: 11 · 2024: 5 · 2023: 14 · 2022: 14 · 2021: 15 · 2020: 12 · 2019: 21 · 2018: 19 · 2017: 12 · 2016: 15 · 2015: 11 · 2014: 10 · 2013: 16 · 2012: 18
FWCI: 16.80
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Max Planck Institute for Plasma Physics (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords: EGFR inhibitors, T790M mutation, irreversible kinase inhibitors, chemogenomic profiling, non-small cell lung cancer, acquired drug resistance, afatinib, PI-103, PI3K/mTOR inhibition, apoptosis, combination therapy, gatekeeper mutation
MeSH terms: Afatinib, Phosphoinositide-3 Kinase Inhibitors, Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Furans, Humans, Lung Neoplasms, Mutation, Pyridines, Pyrimidines, Quinazolines, Blotting, Western, Molecular Structure, Signal Transduction, Cluster Analysis, Apoptosis, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Amino Acid Substitution, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, ErbB Receptors

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Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation.

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