Purpose: Radiation and cetuximab are therapeutics used in management of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of this disease. The purpose of this study was to investigate signaling of the receptor tyrosine kinase AXL in resistance to radiation and cetuximab treatment.Experimental Design: To study AXL signaling in the context of treatment-resistant HNSCC, we used patient-derived xenografts (PDXs) implanted into mice and evaluated the tumor response to AXL inhibition in combination with cetuximab or radiation treatment. To identify molecular mechanisms of how AXL signaling leads to resistance, three tyrosine residues of AXL (Y779, Y821, Y866) were mutated and examined for their sensitivity to cetuximab and/or radiation. Furthermore, reverse phase protein array (RPPA) was employed to analyze the proteomic architecture of signaling pathways in these genetically altered cell lines.Results: Treatment of cetuximab-and radiation-resistant PDXs with AXL inhibitor R428 was sufficient to overcome resistance. RPPA analysis revealed that such resistance emanates from signaling of tyrosine 821 of AXL via the tyrosine kinase c-ABL. In addition, inhibition of c-ABL signaling resensitized cells and tumors to cetuximab or radiotherapy even leading to complete tumor regression without recurrence in head and neck cancer models.Conclusions: Collectively, the studies presented herein suggest that tyrosine 821 of AXL mediates resistance to cetuximab by activation of c-ABL kinase in HNSCC and that targeting of both EGFR and c-ABL leads to a robust antitumor response.

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Bladder cancer is a common urinary tract cancer with a difficult clinical course. With frequent recurrence, patients with a history of bladder cancer often undergo surveillance that involves invasive cystoscopies and biopsies. Not only is this financially burdensome for patients but it is also mentally and physically intensive. Given this predicament, the field has shifted towards the use of non-invasive urinary tests to detect bladder cancer earlier in the disease course and to avoid unnecessary procedures. The first noninvasive test developed was urine cytology; however, that was found to have a low sensitivity, especially for low-grade lesions. There are many tests that are available that utilize common protein biomarkers to enhance the sensitivity of detection. However, many of these tests lack the specificity seen with cytology. With recent technological and research advancements, there are newer detection systems such as RNA sequencing and microfluidics along with novel bladder cancer biomarkers including mRNAs, methylation patterns and exosomes, which have potential to be used in clinical practice. The aim of this review is to highlight established non-invasive bladder cancer diagnostic tests as well as innovative methodologies that are on the horizon for use in bladder cancer detection.

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