Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

Jacqulyne P. Robichaux; Yasir Y. Elamin; R. S.K. Vijayan; Monique B. Nilsson; Lemei Hu; Junqin He; Fahao Zhang; Marlese Pisegna; Alissa Poteete; Huiying Sun; Shuai Li; Ting Chen; Han Han; Marcelo Vailati Negrao; Jordi Rodon Ahnert; Lixia Diao; Jing Wang; Xiuning Le; Funda Meric-Bernstam; Mark Routbort; Brent Roeck; Zane Yang; Victoria M. Raymond; Richard B. Lanman; Garrett M. Frampton; Vincent A. Miller; Alexa B. Schrock; Lee A. Albacker; Kwok kin Wong; Jason B. Cross; John V. Heymach

doi:10.1016/j.ccell.2019.09.001

Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

Jacqulyne P. Robichaux, Yasir Y. Elamin, R. S.K. Vijayan, Monique B. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, Marlese Pisegna, Alissa Poteete, Huiying Sun, Shuai Li, Ting Chen, Han Han, Marcelo Vailati Negrao, Jordi Rodon Ahnert, Lixia Diao, Jing Wang, Xiuning Le, Funda Meric-Bernstam, Mark RoutbortBrent Roeck, Zane Yang, Victoria M. Raymond, Richard B. Lanman, Garrett M. Frampton, Vincent A. Miller, Alexa B. Schrock, Lee A. Albacker, Kwok kin Wong, Jason B. Cross, John V. Heymach

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132 Scopus citations

Abstract

We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

Original language	English (US)
Pages (from-to)	444-457.e7
Journal	Cancer cell
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2019.09.001
State	Published - Oct 14 2019

Keywords

ERBB2 mutant
HER2 mutant
NSCLC
T-DM1
TKI
exon 20
pan-cancer
poziotinib

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Bioinformatics Shared Resource
Research Animal Support Facility
Cytogenetics and Cell Authentication Core

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10.1016/j.ccell.2019.09.001

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Robichaux, J. P., Elamin, Y. Y., Vijayan, R. S. K., Nilsson, M. B., Hu, L., He, J., Zhang, F., Pisegna, M., Poteete, A., Sun, H., Li, S., Chen, T., Han, H., Negrao, M. V., Ahnert, J. R., Diao, L., Wang, J., Le, X., Meric-Bernstam, F., ... Heymach, J. V. (2019). Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity. Cancer cell, 36(4), 444-457.e7. https://doi.org/10.1016/j.ccell.2019.09.001

Robichaux, JP, Elamin, YY , Vijayan, RSK , Nilsson, MB, Hu, L, He, J, Zhang, F, Pisegna, M, Poteete, A, Sun, H, Li, S, Chen, T, Han, H, Negrao, MV , Ahnert, JR , Diao, L , Wang, J , Le, X , Meric-Bernstam, F , Routbort, M, Roeck, B, Yang, Z, Raymond, VM, Lanman, RB, Frampton, GM, Miller, VA, Schrock, AB, Albacker, LA, Wong, KK, Cross, JB & Heymach, JV 2019, 'Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity', Cancer cell, vol. 36, no. 4, pp. 444-457.e7. https://doi.org/10.1016/j.ccell.2019.09.001

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title = "Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity",

abstract = "We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.",

keywords = "ERBB2 mutant, HER2 mutant, NSCLC, T-DM1, TKI, exon 20, pan-cancer, poziotinib",

author = "Robichaux, {Jacqulyne P.} and Elamin, {Yasir Y.} and Vijayan, {R. S.K.} and Nilsson, {Monique B.} and Lemei Hu and Junqin He and Fahao Zhang and Marlese Pisegna and Alissa Poteete and Huiying Sun and Shuai Li and Ting Chen and Han Han and Negrao, {Marcelo Vailati} and Ahnert, {Jordi Rodon} and Lixia Diao and Jing Wang and Xiuning Le and Funda Meric-Bernstam and Mark Routbort and Brent Roeck and Zane Yang and Raymond, {Victoria M.} and Lanman, {Richard B.} and Frampton, {Garrett M.} and Miller, {Vincent A.} and Schrock, {Alexa B.} and Albacker, {Lee A.} and Wong, {Kwok kin} and Cross, {Jason B.} and Heymach, {John V.}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = oct,

day = "14",

doi = "10.1016/j.ccell.2019.09.001",

language = "English (US)",

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T1 - Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

AU - Robichaux, Jacqulyne P.

AU - Elamin, Yasir Y.

AU - Vijayan, R. S.K.

AU - Nilsson, Monique B.

AU - Hu, Lemei

AU - He, Junqin

AU - Zhang, Fahao

AU - Pisegna, Marlese

AU - Poteete, Alissa

AU - Sun, Huiying

AU - Li, Shuai

AU - Chen, Ting

AU - Han, Han

AU - Negrao, Marcelo Vailati

AU - Ahnert, Jordi Rodon

AU - Diao, Lixia

AU - Wang, Jing

AU - Le, Xiuning

AU - Meric-Bernstam, Funda

AU - Routbort, Mark

AU - Roeck, Brent

AU - Yang, Zane

AU - Raymond, Victoria M.

AU - Lanman, Richard B.

AU - Frampton, Garrett M.

AU - Miller, Vincent A.

AU - Schrock, Alexa B.

AU - Albacker, Lee A.

AU - Wong, Kwok kin

AU - Cross, Jason B.

AU - Heymach, John V.

PY - 2019/10/14

Y1 - 2019/10/14

N2 - We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

AB - We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

KW - ERBB2 mutant

KW - HER2 mutant

KW - NSCLC

KW - T-DM1

KW - TKI

KW - exon 20

KW - pan-cancer

KW - poziotinib

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AN - SCOPUS:85072925103

SN - 1535-6108

VL - 36

SP - 444-457.e7

JO - Cancer cell

JF - Cancer cell

IS - 4

ER -

Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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