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Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma
Jihun Kim, … , Jeeyun Lee, Adam J. Bass
Jihun Kim, … , Jeeyun Lee, Adam J. Bass
Published November 17, 2014
Citation Information: J Clin Invest. 2014;124(12):5145-5158. https://doi.org/10.1172/JCI75200.
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Research Article Oncology Article has an altmetric score of 1

Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma

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Abstract

Patients with gastric and esophageal (GE) adenocarcinoma tumors in which the oncogene ERBB2 has been amplified are routinely treated with a combination of cytotoxic chemotherapy and the ERBB2-directed antibody trastuzumab; however, the addition of trastuzumab, even when tested in a selected biomarker-positive patient population, provides only modest survival gains. To investigate the potential reasons for the modest impact of ERBB2-directed therapies, we explored the hypothesis that secondary molecular features of ERBB2-amplified GE adenocarcinomas attenuate the impact of ERBB2 blockade. We analyzed genomic profiles of ERBB2-amplified GE adenocarcinomas and determined that the majority of ERBB2-amplified tumors harbor secondary oncogenic alterations that have the potential to be therapeutically targeted. These secondary events spanned genes involved in cell-cycle regulation as well as phosphatidylinositol-3 kinase and receptor tyrosine kinase signaling. Using ERBB2-amplified cell lines, we demonstrated that secondary oncogenic events could confer resistance to ERBB2-directed therapies. Moreover, this resistance could be overcome by targeting the secondary oncogene in conjunction with ERBB2-directed therapy. EGFR is commonly coamplified with ERBB2, and in the setting of ERBB2 amplification, higher EGFR expression appears to mark tumors with greater sensitivity to dual EGFR/ERBB2 kinase inhibitors. These data suggest that combination inhibitor strategies, guided by secondary events in ERBB2-amplified GE adenocarcinomas, should be evaluated in clinical trials.

Authors

Jihun Kim, Cameron Fox, Shouyong Peng, Mark Pusung, Eirini Pectasides, Eric Matthee, Yong Sang Hong, In-Gu Do, Jiryeon Jang, Aaron R. Thorner, Paul Van Hummelen, Anil K. Rustgi, Kwok-Kin Wong, Zhongren Zhou, Ping Tang, Kyoung-Mee Kim, Jeeyun Lee, Adam J. Bass

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Figure 5

In vitro evidence for the role of the overexpression or amplification of cell-cycle–related genes in ERBB2-amplified GE cell lines.

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In vitro evidence for the role of the overexpression or amplification of...
(A) In vitro lapatinib sensitivity curves for various ERBB2-amplified GE cell lines with or without concomitant overexpression of CCNE1 or CDK6. (B) Growth inhibition of ERBB2/CCNE1-coamplified gastric cancer cell line MKN7 by either lapatinib or AZD5438 alone or by a combination of both. All data are expressed as the percentage of growth relative to that of vehicle-treated control cells. (C) Western blot for p-Rb and total Rb in MKN7 cells treated with increasing concentrations of AZD5438. Cells were harvested for protein extraction 6 hours after drug treatment. (D) Western blots showing MKN7 response to lapatinib at multiple time points. (E) Signaling responses of MKN7 cells to lapatinib alone or in combination with AZD5438. Cells were harvested 1 hour after each treatment. (F) Verification of CDK6 protein expression in our lentiviral expression system by Western blotting. Cells were harvested after blasticidin selection. (G and H) Growth inhibition of OE19 (G) and NCI-N87 (H) cells with or without exogenous CDK6 expression by either lapatinib or palbociclib (PD-0332991) alone or by a combination of both. All cell viability data are expressed as the percentage of growth relative to that of vehicle-treated control cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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