Cetuximab Response of Lung Cancer–Derived EGF Receptor Mutants Is Associated with Asymmetric Dimerization

Cho, Jeonghee; Chen, Liang; Sangji, Naveen F.; Okabe, Takafumi; Yonesaka, Kimio; Francis, Joshua M.; Flavin, Richard; Johnson, William; Kwon, Jihyun; Yu, Shiu Yeh; Greulich, Heidi; Johnson, Bruce E.; Eck, Michael J.; Wong, Kwok-Kin; Meyerson, Matthew

doi:10.1158/0008-5472.can-13-1145

Cited by 87 publications

(105 citation statements)

References 56 publications

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“…Lung tumors were induced in mice harboring EGFR D770insNPG 30 as previously described, and once the mice had obvious lung tumor formation as determined through magnetic resonance imaging (MRI), mice with equal tumor volume received poziotinib (10 mg per kg body weight (mg/kg)), afatinib (20 mg/kg), or vehicle daily for 4 weeks. Tumor volume was determined through MRI, and poziotinib reduced tumor volume by 80% in GEMMs with an EGFR exon 20 mutation (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Robichaux

Elamin

Tan

et al. 2018

Nat Med

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348

373

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Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

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Section: Resultsmentioning

confidence: 99%

“…EGFR D770insNPG and HER2 A775insYVMA GEMMs were generated as previously described 26,30 . Mice were handled in accordance with Good Animal Practices as defined by the Office of Laboratory Animal Welfare and were done with approval from the Dana-Farber Cancer Institute Institutional Animal Care and Use Committee (Boston, MA).…”

Section: Methodsmentioning

confidence: 99%

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Robichaux

Elamin

Tan

et al. 2018

Nat Med

Self Cite

348

373

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“…Soft agar assays were carried out in triplicate as previously described 15, 16. Photographed images of soft agar colonies taken after 2–3 weeks were quantified using Image J software (NIH).…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescence analysis was conducted as previously described 16. In brief, cells were seeded on a 0.16‐mm‐thick 12 mm cover slip (Fisher Scientific) in 24 well plates.…”

Section: Methodsmentioning

confidence: 99%

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

Cho

Kim

et al. 2018

Intl Journal of Cancer

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Aberrant activation of cancer‐derived mutants of the epidermal growth factor receptor (EGFR) is closely associated with cancer pathogenesis and is thought to be mediated through multiple tyrosine phosphorylations within the C‐terminal domain. Here, we examined the consequences of the loss of these C‐terminal phosphorylation sites on cellular transformation in the context of lung‐cancer‐derived L858R, exon 19 deletion and exon 20 insertion mutant EGFR. Oncogenic EGFR mutants with substitution of the 10 potential C‐terminal tyrosine autophosphorylation sites for phenylalanine (CYF10) were still able to promote anchorage‐independent growth in soft agar at levels comparable to the parental L858R or exon19 deletion or exon 20 insertion mutants with intact autophosphorylation sites. Furthermore, these CYF10 mutants retained the ability to transform Ba/F3 cells in the absence of IL‐3. Bead‐based phosphorylation and immunoprecipitation analyses demonstrated that key EGFR‐associated proteins—including Grb2 and PLC‐γ—are neither phosphorylated nor bound to CYF10 mutants in transformed cells. Taken together, we conclude that tyrosine phosphorylation is not required for oncogenic activity of lung‐cancer‐derived mutant EGFR, suggesting these mutants can lead to cellular transformation by an alternative mechanism independent of EGFR phosphorylation.

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“…Cetuximab, a chimeric monoclonal antibody that binds to EGFR, disrupting its dimerization (17), had been proven beneficial in the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN; refs. 18,19), in Kras wild-type metastatic colorectal cancer (mCRC; ref.…”

Section: Introductionmentioning

confidence: 99%

PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients

Rochefordière

Kamal

Floquet

et al. 2015

Clinical Cancer Research

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Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis.Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatinbased radiochemotherapy alone (arm B, n ¼ 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n ¼ 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients.Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P ¼ 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P ¼ 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P ¼ 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18).Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups.

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Cetuximab Response of Lung Cancer–Derived EGF Receptor Mutants Is Associated with Asymmetric Dimerization

Cited by 87 publications

References 56 publications

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients

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