Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial-mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here, we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyperactivation of AKT and sensitized cells to TGFb1-induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKTinhibitory signalosome at TJ and regulates epithelial-mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer.

Aims: Although the benefit of first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) over chemotherapy in EGFR mutation-positive (EGFRm) non-smallcell lung cancer (NSCLC) has been demonstrated in clinical trials, the optimal treatment sequence remains unclear. The objective of our study was to evaluate the cost-effectiveness of dacomitinib in Sweden versus afatinib and osimertinib in first-line treatment of EGFRm NSCLC. Materials and methods: A partitioned survival model was developed with three health states: progression-free, post-progression, and death. Progression-free and overall survival curves were used to inform movements between states. Clinical data were taken from randomized trials, compared via a network meta-analysis (NMA). Utility data were taken from published studies and costs from national Swedish sources. The model used a 15-year time horizon and a Swedish healthcare payer perspective. Sensitivity and scenario analyses were performed. Results: The base-case analysis showed that dacomitinib accrued a total of 2.10 qualityadjusted life years (QALYs) at a total cost of Swedish krona (SEK) 874,615. The incremental cost-effectiveness ratio (ICER) for dacomitinib versus afatinib was SEK 461,556 per QALY gained. The ICER of osimertinib versus dacomitinib, where the small QALY gains of the former came at a high additional cost, was SEK 11,444,709. Deterministic and probabilistic sensitivity analyses confirmed robustness of these results; changes to drug and medical resource use costs and overall survival had the greatest impact on ICER estimates. Limitations: This model is subject to uncertainty associated with extrapolating long-term A c c e p t e d M a n u s c r i p t treatment effects from shorter trial follow-up periods, although this would also be a limitation when using direct comparison or time-dependent hazard ratios. The NMA was limited by the use of indirect comparison although sensitivity analyses supported the robustness of our findings. Conclusions: Our model demonstrated dacomitinib is cost-effective for first-line EGFRm NSCLC treatment in Sweden versus afatinib and osimertinib.

Background Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC) previously treated with a second-generation ALK inhibitor or with first-and second-generation ALK inhibitors. We examined the cost-effectiveness of second-or third-line+ (2L+ or 3L+) lorlatinib in Sweden, versus chemotherapy. Methods A partitioned survival model with three health states (progression free, progressed, or death) was used. Lorlatinib relative efficacy versus chemotherapy was derived using unanchored matching adjusted indirect treatment comparisons from a phase 2 clinical trial. Utility data were derived from the same trial and published studies. Costs (year 2019) were obtained from Swedish national data. Costs and benefits were discounted at 3% per annum using a societal perspective (base case). Model robustness was evaluated with deterministic and probabilistic sensitivity analyses. Results For 2L+, the average discounted total quality-adjusted life year (QALY) gain was 1.29 years. Total incremental costs were Swedish krona (SEK) 731,791, resulting in an incremental cost-effectiveness ratio (ICER) of SEK 566,278 per QALY gained. Non-discounted survival gain amounted to 1.94 years. For 3L+, the average discounted total QALY gain was 1.25 years. Total incremental costs were SEK 754,801, resulting in an ICER of SEK 603,934 per QALY gained. Nondiscounted survival gain was 1.88 years. Sensitivity analyses were consistent. Conclusions ICERs ranged from SEK 421,000 to SEK 384,066 less than the boundary for a cost-effective treatment for a high-severity disease in Sweden (SEK 988,000), suggesting 2L+ or 3L+ lorlatinib is a cost-effective treatment for ALKpositive NSCLC versus chemotherapy.

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