IN THIS ISSUE APC Mutation Position Dictates Effect of Tankyrase Inhibition in Colorectal Cancer • The effects of APC mutations, which in- • New animal models, human cells, and or- • Cases with different mutations in crease WNT signaling in colorectal can- ganoids were used to circumvent issues the same gene should be evaluated cer, can be reversed by TNKS inhibition . with mouse colorectal cancer models . separately for therapeutic response . Hyperactive WNT signaling is tumor growth in vivo. However, whether TNKS inhibition seen in most colorectal cancers, was effective depended on the mechanism of APC disrup- and inactivating mutations in the tion: APC mutants with truncations in the mutation cluster tumor suppressor adenomatous region were still able to regulate β-catenin and responded to polyposis coli (APC)—a scaffold TNKS blockade, whereas this was not the case when there protein mediating the formation were truncations earlier in the sequence. Truncations in the of the destruction complex (DC) mutation cluster region are commonly observed in patients, that facilitates β-catenin degrada- whereas the earlier truncations are present in commonly used tion—is the cause in 80% of such mouse models. Collectively, these results indicate that TNKS cases. Restoring DC activity (and, inhibition can restore control of WNT signaling in some thus, normal WNT signaling) in the context of inactivated APC-mutant cases and illustrate that different mutations in APC is possible through pharmacologic inhibition of tanky- the same gene, even those causing the same phenotype (in rase (TNKS) 1 and 2, which are functionally redundant. Using this case, WNT hyperactivation), can respond differently to APC-mutant animal models, human cells, and ex vivo orga- targeted therapies. n noid cultures, Schatoff and colleagues found that TNKS inhi- bition suppressed hyperactive WNT signaling and controlled See article, p. 1358. Olaparib with Temozolomide Shows Efficacy in Small-Cell Lung Cancer • Olaparib with temozolomide (OT) • A co-clinical trial using patient- • Further trials of OT or similar com- showed preliminary evidence of derived xenografts identified bio- binations using doses defined in efficacy in small-cell lung cancer . markers for treatment response . this study are warranted . The combination of poly 4.3 months, and after a median follow-up period of (ADP-ribose) polymerase (PARP) 7.1 months, the median progression-free survival was inhibitors with DNA-damaging 4.2 months, and the median overall survival was 8.5 months. agents is a treatment prospect of Experiments using patient-derived xenograft models faith- interest in small-cell lung cancer fully recapitulated clinical data from the patients. The PDX (SCLC). Farago and colleagues models revealed that sensitivity to standard first-line therapy conducted a single-arm phase I/II with etoposide and platinum (EP) correlated with response clinical trial of the FDA-approved to OT. Further, sensitivity to EP and OT was associated PARP inhibitor olaparib with with increased transcription of inflammatory-response gene the DNA-alkylating drug temo- sets, whereas resistance to EP and OT was correlated with zolomide (OT) in 50 patients with relapsed SCLC. The pri- expression of MYC-regulated transcripts. The PDX models mary objective for the phase I portion of the trial was to also defined possible biomarkers for response to OT, includ- determine the dose for the phase II portion of the trial, ing CEACAM1 (encoding CD66B), OAS1, TNFSF10 (encoding which had the goal of assessing efficacy. The overall response TRAIL), and TGIF1. This study provides a basis for further rate (ORR) in the 48 evaluable patients was 41.7% (20/48), trials of OT and possibly other combinations of PARP inhibi- with 20 patients exhibiting a confirmed partial response tors with DNA-damaging agents. n and an additional 4 patients experiencing an unconfirmed partial response. The median duration of response was See article, p. 1372. OCTOber 2019 CANCER DISCOVERY | 1325 Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2019 American Association for Cancer Research. IN THIS ISSUE Trial Data Supports Biomarker-Based Treatment in Gastric Cancer • Biomarker-based treatment was • Patients with MET amplifications • The PD-L1 status of patients associated with improved response receiving savolitinib exhibited the treated with selumetinib and in patients with gastric cancer . most promising responses . docetaxel changed over time . Recent studies have revealed still predicted better response. The most promising results heterogeneity in the genomic were seen in the patient group with MET amplifications alterations found in gastric can- assigned to monotherapy with the reversible MET kinase cer. In the VIKTORY trial, Lee and inhibitor savolitinib, with an overall response rate of 50% colleagues classified 772 patients (10/20 patients). In this group, higher MET copy number was with metastatic gastric cancer associated with increased probability of response, a phenom- who had undergone one round enon that has also been observed in patients with gastric can- of cytotoxic chemotherapy into cer with HER2 or EGFR amplifications treated with HER2- or eight biomarker-based groups, EGFR-targeted therapies. Additionally, it was observed in a when possible, and matched small group of patients that PD-L1 status changed with time them with clinical trials accordingly. Compared with a cohort following treatment with selumetinib and docetaxel, a finding not assigned to trials based on biomarkers, patients matched that may have implications for use of PD-L1 as a predictive with treatments based on biomarkers had improved response biomarker for immunotherapy in gastric cancer. Collectively, rates (median overall survival of 9.8 versus 6.9 months; median these results highlight the potential utility of biomarker-based progression-free survival of 5.7 versus 3.8 months). After cor- treatment for gastric cancer, perhaps especially in cases associ- recting for prognostic factors such as age, gender, number of ated with MET amplification. n organs involved, Epstein–Barr virus status, mismatch-repair status, and performance status, biomarker-based treatment See article, p. 1388. Langerhans Cell Histiocytosis Exhibits a Cellular Developmental Hierarchy • Langerhans cell histiocytosis (LCH) • LCH cells were classified, including a • The results support a developmen- lesions exhibited cellular and proliferative compartment, defining tal hierarchy in LCH lesions and pro- molecular heterogeneity . cell types with specific properties . vide insight into LCH progression . Langerhans cell histiocytosis ciated with the cell cycle, and genes associated with DNA (LCH) is a rare, MAPK pathway– repair. These findings support the characterization of LCH driven hematopoietic disorder as both an inflammatory disease and a cancer. The single-cell that lies between traditionally resolution of the dataset enabled analysis of the cellular and defined cancers and inflamma- molecular heterogeneity among LCH cells, which revealed tory diseases and exhibits marked a developmental hierarchy within LCH lesions; specifically, clinical heterogeneity. Through a fourteen distinguishable cell categories ranging from low to single-cell transcriptomic analy- high differentiation status were represented in samples from sis of biopsies from seven LCH all seven lesions. ATAC-seq experiments showed that there lesions from different sites, were characteristic patterns of chromatin accessibility for Halbritter, Farlik, and colleagues developed a cellular and each LCH cell type, and specific gene-regulatory networks molecular characterization of LCH. In addition to LCH cells, distinguished each cell type, supporting the observed devel- multiple distinct clusters of immune cells were identified, opmental hierarchy of LCH cell types. Collectively, these including T cells, B cells, macrophages, and dendritic cells. findings provide evidence for a high degree of heterogeneity LCH cells exhibited high expression of genes previously iden- within LCH lesions and lay the groundwork for further stud- tified as being specifically upregulated in LCH (e.g.,MMP9 ) ies of the developmental progression of LCH cells. n as well as genes important for antigen presentation, genes for HLA-complex members, MYC-associated genes, genes asso- See article, p. 1406. 1326 | CANCER DISCOVERY OCTOBER 2019 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2019 American Association for Cancer Research. IN THIS ISSUE PD-L1–Expressing NK Cells May Underlie Anti–PD-L1 Response in PD-L1− Tumors • Contact between healthy NK cells • High PD-L1 expression by NK cells • PD-L1 expression in human NK cells and myeloid leukemia cells trig- in patients with AML was associ- was regulated by the PI3K/AKT gered PD-L1 expression on NK cells . ated with complete remission . signaling pathway . Blockade of programmed death was associated with an increased chance of complete remis- ligand 1 (PD-L1) with monoclo- sion (CR). Exposure to the anti–PD-L1 therapy atezolizumab nal antibodies has been success- enhanced the activity of NK cells, and in vivo experiments fully used to treat PD-L1+ tumors; showed that mouse NK cells with high PD-L1 expression however, for unknown reasons, had increased antitumor effects. Surprisingly, this mecha- PD-L1− tumors also sometimes nism appeared to be PD-1 independent. In an orthotopic respond to anti–PD-L1 therapy. mouse model, atezolizumab