Hiromichi Ebi

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complexes and amplified expression of SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) complexes that drive an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program. The small molecule SUMOylation inhibitor, TAK-981, de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting SS models away from SS18::SSX-driven transcription. The result is DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergizes with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability.

The FIRST‐Dx study prospectively evaluated the clinical utility of the comprehensive genomic profiling (CGP) test (FoundationOne CDx) in the first‐line setting for patients with chemotherapy‐naïve advanced solid tumors (gastrointestinal, biliary, pancreatic, lung, breast, gynecologic, melanoma) in six hospitals in Japan. Here, we report the results of the 1‐year interim analysis of the follow‐up study about the clinical benefits provided by the upfront CGP test. The primary endpoint was overall survival (OS), and secondary endpoints were the proportion of patients who actually received molecular‐based recommended therapy (MBRT) determined by the molecular tumor board, best overall response rate (ORR) in each line of therapy, and progression‐free survival (PFS) ratio (PFS on MBRT/PFS on the first‐line therapy). Data from 172 patients with a median follow‐up of 15.1 months (range: 0.1–21.5 months) were available. The median OS was not reached. Thirty‐nine patients (22.7%) received MBRT during this follow‐up period. ORR in first‐line therapy was 56.3% in the MBRT group (n = 16) vs. 42.3% in the non‐MBRT group (n = 137), and in the second‐line was 26.3% in the MBRT group (n = 19) vs. 17.1% in the non‐MBRT group (n = 82). Regarding the PFS ratio of second‐line MBRT (n = 12), the median PFS ratio was 1.1, and four patients (33.3%) had a ratio ≥ 1.3, indicating that MBRT might be effective in changing the clinical outcome. The findings of this study imply that CGP testing before the standard of care for patients with advanced solid tumors could prove to be a clinically beneficial strategy for guiding subsequent precision anticancer treatments.Trial Registration: Japan Registry of Clinical Trials (jRCT) ID: jRCT1050220041

KRAS was long deemed undruggable until the discovery of the switch‐II pocket facilitated the development of specific KRAS inhibitors. Despite their introduction into clinical practice, resistance mechanisms can limit their effectiveness. Initially, tumors rely on mutant KRAS, but as they progress, they may shift to alternative pathways, resulting in intrinsic resistance. This resistance can stem from mechanisms like epithelial‐to‐mesenchymal transition (EMT), YAP activation, or KEAP1 mutations. KRAS inhibition often triggers cellular rewiring to counteract therapeutic pressure. For instance, feedback reactivation of signaling pathways such as MAPK, mediated by receptor tyrosine kinases, supports tumor cell survival. Inhibiting KRAS disrupts protein homeostasis, but reactivation of MAPK or AKT can restore it, aiding tumor cell survival. KRAS inhibition also causes metabolic reprogramming and protein re‐localization. The re‐localization of E‐cadherin and Scribble from the membrane to the cytosol causes YAP to translocate to the nucleus, where it drives MRAS transcription, leading to MAPK reactivation. Emerging evidence indicates that changes in cell identity, such as mucinous differentiation, shifts from alveolar type 2 to type 1 cells, or lineage switching from adenocarcinoma to squamous cell carcinoma, also contribute to resistance. In addition to these nongenetic mechanisms, secondary mutations in KRAS or alterations in upstream/downstream signaling proteins can cause acquired resistance. Secondary mutations in the switch‐II pocket disrupt drug binding, and known oncogenic mutations affect drug efficacy. Overcoming these resistance mechanisms involves enhancing the efficacy of drugs targeting mutant KRAS, developing broad‐spectrum inhibitors, combining therapies targeting multiple pathways, and integrating immune checkpoint inhibitors.

Background/Objectives: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While ARAF gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics. Methods: We conducted a single-center retrospective analysis of the presence of ARAF amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. ARAF amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with ARAF amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC). Results: ARAF amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. ARAF amplification was dominantly observed in female patients with EGFR exon 19 deletion. All ARAF-amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where ARAF amplification correlated with a histological transformation to SCLC. Conclusions: ARAF amplification was identified in 5–8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.

The interim analysis of the CIRCULATE-Japan GALAXY observational study demonstrated the association of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection with recurrence risk and benefit from adjuvant chemotherapy (ACT) in resectable colorectal cancer (CRC). This updated analysis with a 23-month median follow-up, including 2,240 patients with stage II-III colon cancer or stage IV CRC, reinforces the prognostic value of ctDNA positivity during the MRD window with significantly inferior disease-free survival (DFS; hazard ratio (HR): 11.99, P < 0.0001) and overall survival (OS; HR: 9.68, P < 0.0001). In patients who experienced recurrence, ctDNA positivity correlated with shorter OS (HR: 2.71, P < 0.0001). The significantly shorter DFS in MRD-positive patients was consistent across actionable biomarker subsets. Sustained ctDNA clearance in response to ACT was an indicator of favorable DFS and OS compared to transient clearance (24-month DFS: 89.0% versus 3.3%; 24-month OS: 100.0% versus 82.3%). True spontaneous clearance rate with no clinical recurrence was 1.9% (2/105). Overall, our findings provide evidence for the utility of ctDNA monitoring for post-resection recurrence and mortality risk stratification that could be used for guiding adjuvant therapy.