Effects of HER family-targeting tyrosine kinase inhibitors on antibody-dependent cell-mediated cytotoxicity in HER2-expressing breast cancer

a.sfakia shared this article with you from Inoreader Effects of HER family-targeting tyrosine kinase inhibitors on antibody-dependent cell-mediated cytotoxicity in HER2-expressing breast cancer Via Clinical Cancer Research Online First Articles Purpose: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs) like lapatinib may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and NK cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, neratinib) to alter HER2/immune-related protein levels in pre-clinical models of HER2+ and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC. Experimental Design: Pre-clinical studies (proliferation assays, Western blot, high content analysis, flow cytometry) employed HER2+ (SKBR3, HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, CAL-51) breast cancer cell lines. NCT00524303 provided RPPA-determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (Cibersort/MCP-counter) post-neo-adjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow-cytometry-based protocols. Results: Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all pre-clinical models. Single agent lapatinib increased HER2 or EGFR levels in 10/11 (91%) tumor samples. NK cell signatures increased post-therapy (p=0.03) and associated with trastuzumab response (p=0.01). TKI treatment altered mAb-induced NK cell-mediated ADCC in vitro but it did not consistently correlate with HER2 expression in HER2+ or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone. Conclusions: TKIs differentially alter tumor cell phenotype which can impact NK cell-mediated response to co-administered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.< /p> View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.