Abstract

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.

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