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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.

Delirium is associated with cognitive decline and subsequent dementia, and rises in plasma total Tau (tTau) and neurofilament light (NfL), providing links to Amyloid-Tau-Neurodegeneration (ATN) pathophysiology. We investigated whether changes in delirium severity after surgery correlated with changes in cerebrospinal fluid (CSF) ATN biomarkers. Thirty-two thoracic vascular surgical patients were recruited into a prospective biomarker cohort study with assessment of delirium severity and incidence (NCT02926417). CSF (n = 54) and plasma (n = 118) samples were sent for biomarker analysis for tTau, phosphorylated tau-181 (pTau) (plasma n = 53), NfL, and amyloid-β 42/40 ratio (Ab42/40-ratio). The primary outcome was the correlation of preoperative to postoperative change in ATN biomarkers with the highest postoperative Delirium Rating Scale-98 score. CSF and plasma biomarkers all increased postoperatively (all P < .05, n = 13 paired preoperative-postoperative samples). Delirium severity was associated with peak changes in CSF tTau (P = .007, r = 0.710) and pTau (P = .01, r = 0.667) but not NfL (P = .09, rho = 0.491) or Ab42/40-ratio (P = 0.18, rho = 0.394). Sensitivity analysis with exclusion of subjects with putative spinal cord ischaemia shifted the NfL result to significance (P < .001, rho = .847). Our data show that changes in tau and biomarkers of neurodegeneration in the CSF are associated with delirium severity. These data should be considered hypothesis generating and future studies should identify if these changes are robust to confounding.

Altered predictive coding may underlie the reduced auditory mismatch negativity amplitude observed in patients with dementia. We hypothesized that accumulating dementia-associated pathologies, including amyloid and tau, lead to disturbed predictions of our sensory environment. This would manifest as increased reliance on “observed” sensory information with an associated increase in feedforward, and decrease in feedback, signaling. To test this hypothesis, we studied a cross-sectional cohort of participants who underwent positron emission tomography imaging and high-density EEG during an odd-ball paradigm, and used dynamic casual modeling and Bayesian statistics to make inferences about the neuronal architectures (generators) and mechanisms (effective connectivity) underlying the observed auditory evoked responses. Amyloid-β imaging with [C-11] Pittsburgh Compound-B PET were qualitatively rated using established criteria. Tau-positive PET scans, with [F-18]MK6240, were defined by a MK-6240 standardized uptake value ratio positivity threshold at two standard deviations above the mean of the Amyloid(−) group in the entorhinal cortex (entorhinal MK-6240 SUVR > 1.27). The cross-sectional cohort included a total of 56 participants (9 and 13 participants in the Tau(+) and Amyloid(+) subgroups, respectively: age interquartile range of [73.50 - 75.34] and [70.5–75.34] years, 56% and 69% females, respectively; 46 and 43 participants in the Tau(-) and Amyloid(-) subgroups, respectively: age interquartile range of [62.72–72.5] and [62.64–72.48] years, 67% and 65% females, respectively). Mismatch negativity amplitudes were significantly smaller in Tau+ subgroup than Tau- subgroup (cluster statistics corrected for multiple comparisons: p = 0.028). Dynamic causal modelling showed that tau pathology was associated with increased feedforward connectivity and decreased feedback connectivity, with increased excitability of superior temporal gyrus but not inferior frontal regions. This effect on superior temporal gyrus was consistent with the distribution of tau disease on PET in these participants, indicating that the observed differences in mismatch negativity reflect pathological changes evolving in preclinical dementia. Exclusion of participants with diagnosed mild cognitive impairment or dementia did not affect the results. These observational data provide proof of concept that abnormalities in predictive coding may be detected in the preclinical phase of Alzheimer’s disease. This framework also provides a construct to understand how progressive impairments lead to loss of orientation to the sensory world in dementia. Based on our modeling results, plus animal models indicating that Alzheimer’s disease pathologies produce hyperexcitability of higher cortical regions through local disinhibition, mismatch negativity might be a useful monitor to deploy as strategies that target interneuron dysfunction are developed.