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<p>The recent successes of HER2-targeting agents, even in tumors characterized by FDA-approved molecular testing as HER2-negative or non-amplified, have underscored the limitations of current diagnostic approaches for accurately identifying patients with actionable HER2/EGFR activation/phosphorylation. We therefore performed a multi-omic investigation integrating clinical next-generation sequencing with a CLIA-certified reverse-phase protein array (RPPA) assay and laser microdissection-enriched tumor samples to characterize <i>ERBB2</i>/HER2 at the DNA, RNA, protein, and phosphoprotein level in patients with advanced pan-cancer solid tumor malignancies. Functional pathway activation mapping by RPPA revealed several patients with <i>ERBB2</i> genomic or transcriptomic alterations and/or HER2<sup>Total</sup>-positivity by immunohistochemistry who exhibited no significant HER2<sup>Y1248</sup> activation/phosphorylation. In contrast, other patients lacking <i>ERBB2</i> genomic/transcriptomic alterations demonstrated significant HER2<sup>Y1248</sup> activation/phosphorylation with co-activation of EGFR<sup>Y1173</sup>, a marker associated with prognostic significance. Our results highlight the weak concordance between <i>ERBB2</i> genomic/transcriptomic alterations and downstream activation of HER family signaling and support the inclusion of functional proteomic/phosphoproteomic analysis as an essential component of precision oncology pipelines to more accurately guide selection of HER2- and EGFR-targeted therapies.</p>

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Pan-cancer multi-omic ERBB2-HER2 characterization using next-generation sequencing and quantitative proteomics

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月5日

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  • Allison L. Hunt,
  • Jamie Randall,
  • Jonathan D. Ogata,
  • Laura Johnston,
  • Whitney Swain,
  • Savannah Melvin,
  • Meenakshi Sharma,
  • Valerie Calvert,
  • G. Larry Maxwell,
  • Nicholas W. Bateman,
  • Emanuel F. Petricoin,
  • Thomas P. Conrads,
  • Timothy L. Cannon

摘要

The recent successes of HER2-targeting agents, even in tumors characterized by FDA-approved molecular testing as HER2-negative or non-amplified, have underscored the limitations of current diagnostic approaches for accurately identifying patients with actionable HER2/EGFR activation/phosphorylation. We therefore performed a multi-omic investigation integrating clinical next-generation sequencing with a CLIA-certified reverse-phase protein array (RPPA) assay and laser microdissection-enriched tumor samples to characterize ERBB2/HER2 at the DNA, RNA, protein, and phosphoprotein level in patients with advanced pan-cancer solid tumor malignancies. Functional pathway activation mapping by RPPA revealed several patients with ERBB2 genomic or transcriptomic alterations and/or HER2Total-positivity by immunohistochemistry who exhibited no significant HER2Y1248 activation/phosphorylation. In contrast, other patients lacking ERBB2 genomic/transcriptomic alterations demonstrated significant HER2Y1248 activation/phosphorylation with co-activation of EGFRY1173, a marker associated with prognostic significance. Our results highlight the weak concordance between ERBB2 genomic/transcriptomic alterations and downstream activation of HER family signaling and support the inclusion of functional proteomic/phosphoproteomic analysis as an essential component of precision oncology pipelines to more accurately guide selection of HER2- and EGFR-targeted therapies.