👤 Rebecca Redman

Macroautophagy/autophagy is a stress-responsive lysosomal catabolic pathway that promotes cellular homeostasis and tumor cell survival, but its role in breast cancer progression and metastasis remains unclear. Here, we show that a brain-specific serine/threonine protein kinase, BRSK2, a marker of aggressive metastatic disease in breast cancer patients, is crucial in regulating autophagy. BRSK2 is overexpressed in aggressive cancer and is associated with reduced disease-specific survival. BRSK2 also regulates basal autophagy and activates AKT, STAT3, and NF-κB-mediated cancer cell survival pathways. In addition, BRSK2 overexpression increases the levels of inflammatory cytokines and chemokines in breast cancer cells. Downregulation of BRSK2 using specific siRNAs or the BRSK2 kinase small-molecule inhibitor GW296115 markedly reduced nutrient-deprivation stress-mediated autophagy, cell growth, and metastatic potential, and enhanced breast cancer cell apoptosis. Endogenous BRSK2 is associated with the Vps34-class III PI3K-Beclin-1-ATG14 autophagy signaling complexes that could protect cancer cells from nutrient-deprivation stress. Our findings demonstrate the key role of the BRSK2-mediated protective autophagy and cell growth and survival under nutrient deprivation stress via survival signals, e.g., PI3K/AKT or STAT3-NF-kB, in aggressive breast cancer cells. Show less

This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. See related commentary by Hage Chehade et al., p. 4549. Show less

Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non-small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8+ T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC patient cohort. The results revealed the presence of a myeloid-rich subgroup, which was devoid of CD4+ and CD8+ T cells. Of all myeloid cell types assessed, neutrophils were the most highly associated with the myeloid phenotype. Additionally, the ratio of CD8+ T cells to neutrophils (CD8/PMN) within the tumor mass optimally distinguished between active and myeloid cases. This ratio was also capable of showing the separation of patients responsive to ICI therapy from those with stable or progressive disease in 2 independent cohorts. Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-γ-responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes. Show less