Genomic correlate of exceptional erlotinib response in head and neck squamous cell carcinoma

Eliezer M. Van Allen, Vivian W.Y. Lui, Ann Marie Egloff, Eva M. Goetz, Hua Li, Jonas T. Johnson, Umamaheswar Duvvuri, Julie E. Bauman, Nicolas Stransky, Yan Zeng, Breean R. Gilbert, Kelsey P. Pendleton, Lin Wang, Simion Chiosea, Carrie Sougnez, Nikhil Wagle, Fan Zhang, Yu Du, David Close, Paul A. JohnstonAaron McKenna, Scott L. Carter, Todd R. Golub, Gad Getz, Gordon Mills, Levi A. Garraway, Jennifer R. Grandis

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

IMPORTANCE: Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response. OBJECTIVE: To determine a mechanism of exceptional response to erlotinib therapy in HNSCC. DESIGN, SETTING, AND PARTICIPANTS: Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response. INTERVENTION: A brief course of erlotinib monotherapy followed by surgical resection. MAIN OUTCOMES AND MEASURES: Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants. RESULTS: No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells. CONCLUSIONS AND RELEVANCE: Selective erlotinib use in HNSCC may be informed by precision oncology approaches.

Original languageEnglish (US)
Pages (from-to)238-244
Number of pages7
JournalJAMA oncology
Volume1
Issue number2
DOIs
StatePublished - May 1 2015
Externally publishedYes

Fingerprint

Epidermal Growth Factor Receptor
Neoplasms
Carcinoma, squamous cell of head and neck
Erlotinib Hydrochloride
Exome
Protein-Tyrosine Kinases
Lung Neoplasms
Randomized Controlled Trials
Phosphorylation
Clinical Trials
Mutation
DNA
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Van Allen, E. M., Lui, V. W. Y., Egloff, A. M., Goetz, E. M., Li, H., Johnson, J. T., ... Grandis, J. R. (2015). Genomic correlate of exceptional erlotinib response in head and neck squamous cell carcinoma. JAMA oncology, 1(2), 238-244. https://doi.org/10.1001/jamaoncol.2015.34

Genomic correlate of exceptional erlotinib response in head and neck squamous cell carcinoma. / Van Allen, Eliezer M.; Lui, Vivian W.Y.; Egloff, Ann Marie; Goetz, Eva M.; Li, Hua; Johnson, Jonas T.; Duvvuri, Umamaheswar; Bauman, Julie E.; Stransky, Nicolas; Zeng, Yan; Gilbert, Breean R.; Pendleton, Kelsey P.; Wang, Lin; Chiosea, Simion; Sougnez, Carrie; Wagle, Nikhil; Zhang, Fan; Du, Yu; Close, David; Johnston, Paul A.; McKenna, Aaron; Carter, Scott L.; Golub, Todd R.; Getz, Gad; Mills, Gordon; Garraway, Levi A.; Grandis, Jennifer R.

In: JAMA oncology, Vol. 1, No. 2, 01.05.2015, p. 238-244.

Research output: Contribution to journalArticle

Van Allen, EM, Lui, VWY, Egloff, AM, Goetz, EM, Li, H, Johnson, JT, Duvvuri, U, Bauman, JE, Stransky, N, Zeng, Y, Gilbert, BR, Pendleton, KP, Wang, L, Chiosea, S, Sougnez, C, Wagle, N, Zhang, F, Du, Y, Close, D, Johnston, PA, McKenna, A, Carter, SL, Golub, TR, Getz, G, Mills, G, Garraway, LA & Grandis, JR 2015, 'Genomic correlate of exceptional erlotinib response in head and neck squamous cell carcinoma', JAMA oncology, vol. 1, no. 2, pp. 238-244. https://doi.org/10.1001/jamaoncol.2015.34
Van Allen, Eliezer M. ; Lui, Vivian W.Y. ; Egloff, Ann Marie ; Goetz, Eva M. ; Li, Hua ; Johnson, Jonas T. ; Duvvuri, Umamaheswar ; Bauman, Julie E. ; Stransky, Nicolas ; Zeng, Yan ; Gilbert, Breean R. ; Pendleton, Kelsey P. ; Wang, Lin ; Chiosea, Simion ; Sougnez, Carrie ; Wagle, Nikhil ; Zhang, Fan ; Du, Yu ; Close, David ; Johnston, Paul A. ; McKenna, Aaron ; Carter, Scott L. ; Golub, Todd R. ; Getz, Gad ; Mills, Gordon ; Garraway, Levi A. ; Grandis, Jennifer R. / Genomic correlate of exceptional erlotinib response in head and neck squamous cell carcinoma. In: JAMA oncology. 2015 ; Vol. 1, No. 2. pp. 238-244.
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AU - Van Allen, Eliezer M.

AU - Lui, Vivian W.Y.

AU - Egloff, Ann Marie

AU - Goetz, Eva M.

AU - Li, Hua

AU - Johnson, Jonas T.

AU - Duvvuri, Umamaheswar

AU - Bauman, Julie E.

AU - Stransky, Nicolas

AU - Zeng, Yan

AU - Gilbert, Breean R.

AU - Pendleton, Kelsey P.

AU - Wang, Lin

AU - Chiosea, Simion

AU - Sougnez, Carrie

AU - Wagle, Nikhil

AU - Zhang, Fan

AU - Du, Yu

AU - Close, David

AU - Johnston, Paul A.

AU - McKenna, Aaron

AU - Carter, Scott L.

AU - Golub, Todd R.

AU - Getz, Gad

AU - Mills, Gordon

AU - Garraway, Levi A.

AU - Grandis, Jennifer R.

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N2 - IMPORTANCE: Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response. OBJECTIVE: To determine a mechanism of exceptional response to erlotinib therapy in HNSCC. DESIGN, SETTING, AND PARTICIPANTS: Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response. INTERVENTION: A brief course of erlotinib monotherapy followed by surgical resection. MAIN OUTCOMES AND MEASURES: Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants. RESULTS: No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells. CONCLUSIONS AND RELEVANCE: Selective erlotinib use in HNSCC may be informed by precision oncology approaches.

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