Abstract
<div>AbstractPurpose:<p>Naturally occurring primary canine lung cancers share clinicopathologic features with human lung cancers in never-smokers, but the genetic underpinnings of canine lung cancer are unknown. We have charted the genomic landscape of canine lung cancer and performed functional characterization of novel, recurrent <i>HER2 (ERBB2)</i> mutations occurring in canine pulmonary adenocarcinoma (cPAC).</p>Experimental Design:<p>We performed multiplatform genomic sequencing of 88 primary canine lung tumors or cell lines. Additionally, in cPAC cell lines, we performed functional characterization of HER2 signaling and evaluated mutation-dependent HER2 inhibitor drug dose-response.</p>Results:<p>We discovered somatic, coding <i>HER2</i> point mutations in 38% of cPACs (28/74), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. The majority (93%) of <i>HER2</i> mutations were hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other <i>HER2</i> mutations were located in the extracellular domain and TMD. <i>HER2</i><sup>V659E</sup> was detected in the plasma of 33% (2/6) of dogs with localized <i>HER2</i><sup>V659E</sup> tumors. <i>HER2</i><sup>V659E</sup> cPAC cell lines displayed constitutive phosphorylation of AKT and significantly higher sensitivity to the HER2 inhibitors lapatinib and neratinib relative to <i>HER2</i>-wild-type cell lines (IC<sub>50</sub> < 200 nmol/L in <i>HER2</i><sup>V659E</sup> vs. IC<sub>50</sub> > 2,500 nmol/L in <i>HER2</i><sup>WT</sup>).</p>Conclusions:<p>This study creates a foundation for molecular understanding of and drug development for canine lung cancer. These data also establish molecular contexts for comparative studies in dogs and humans of low mutation burden, never-smoker lung cancer, and mutant HER2 function and inhibition.</p></div>
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