Finally, there might be other mechanisms of altering oncoprotein function/activity that NGS diagnostic is not able to identify. known driver mutations are found, its limitation is the dependence on driver mutations as predictors for response. To complement Thrombin Receptor Activator for Peptide 5 (TRAP-5) the genotype approach, we hypothesize that a phosphoarray platform is usually equally capable of personalizing kinase inhibitor therapy. We selected head and neck squamous cell carcinoma as the cancer model to test our hypothesis. Using the receptor tyrosine kinase phosphoarray, we identified the phosphorylation profiles of 49 different tyrosine kinase receptors in five different head and neck malignancy cell lines. Based on these results, we tested the cell line response to the corresponding kinase inhibitor therapy. We found that this phosphoarray accurately informed the kinase inhibitor response profile of the cell lines. Next, we decided the phosphorylation profiles of 39 head and neck cancer patient derived xenografts. We Thrombin Receptor Activator for Peptide 5 (TRAP-5) found that absent phosphorylated EGFR signal predicted primary resistance to cetuximab treatment in the xenografts without phosphorylated ErbB2. Meanwhile, absent ErbB2 signaling in the xenografts with phosphorylated EGFR is usually associated with a higher likelihood of response to cetuximab. In summary, the phosphoarray technology has the potential to become a new diagnostic platform for personalized cancer therapy. strong class=”kwd-title” Keywords: phosphoarray, head and neck squamous cell carcinoma, kinase inhibitors, personalized medicine, cetuximab response Introduction Imatinib is the first tyrosine kinase inhibitor (TKI) that directly targeted an oncogenic driver mutant. This drug showed unprecedented success in the treatment of chronic myleogenous leukemia (1). Since then, many kinase inhibitors targeting different oncogenic kinases were developed. A few of these drugs showed equally impressive efficacy, for instance, crizotinib for the non small cell lung cancers (NSCLC) that harbored the EML4-ALK translocation (2), vemurafenib for the BRAF V600E mutated melanoma (3), erlotinib for the NSCLC that harbored activating EGFR kinase mutations (4) or vandetanib for the hereditary medullary thyroid cancer with underlying RET mutation (5). Like imatinib, the common theme around these success stories is that the TKIs specifically targeted the oncogenic Thrombin Receptor Activator for Peptide 5 (TRAP-5) mutants that drive the underlying cancers. Thus, recent effort has been focused on profiling the genetic scenery of tumors to identify potential druggable targets, thereby increasing the efficacy of kinase Mouse monoclonal to P504S. AMACR has been recently described as prostate cancerspecific gene that encodes a protein involved in the betaoxidation of branched chain fatty acids. Expression of AMARC protein is found in prostatic adenocarcinoma but not in benign prostatic tissue. It stains premalignant lesions of prostate:highgrade prostatic intraepithelial neoplasia ,PIN) and atypical adenomatous hyperplasia. inhibitor therapies. With the rapid advance in sequencing technologies, high throughput screening of mutation drivers by next generation sequencing (NGS) is now a commercially available service for personalized cancer therapy. There are many anecdotal cases that utilized the NGS platform to identify driver mutations in cancer patients for novel TKI therapy (6C10). In some cases, the diagnostic was successful in personalizing the right TKIs for the right patients. For instance, when a 41 12 months old woman with refractory, progressive sarcoma ran out of therapeutic options, NGS identified a novel TRK receptor fusion product, LMNA-NTRK1, in her initial tumor. She was subsequently enrolled in a phase I trial of a new pan-TRK inhibitor, LOXO-101. After five cycles of LOXO-101, there was complete resolution of her metastatic diseases (11). Similarly, after MET exon 14 mutations were identified in 0.6% of lung adenocarcinoma by NGS, three patients with tumors harboring these MET mutants were treated with MET directed therapies via clinical trials. All three exhibited partial responses (12). Despite these success stories, the NGS platform has limitations as a personalized diagnostic. First, it might reveal many passenger mutations that are not drivers of the tumor. Second, bearing driver mutants does not necessarily translate into response to the corresponding TKIs. For instance, vemurafenib did not produce a dramatic response in the treatment of BRAF V600E mutated colorectal cancer (13). Third, low mutation rates in some cancers like pediatric tumors (14) might limit the usefulness of NGS as a personalized diagnostic. Fourth, there might not be mutation drivers of a known target in the tumor. For example, EGFR is a known target for head and neck squamous cell carcinomas (HNSCC), but HNSCC rarely carried activating EGFR kinase mutations (15, 16). Finally, there might be other mechanisms of altering oncoprotein function/activity that NGS diagnostic is not able to identify. Such mechanisms might include overexpression, impaired degradation, defective negative feedback.