Cancer neoantigens and neoantigen-specific T cells can be identified from blood alone, using circulating tumor DNA (ctDNA) sequencing of immune-cell analysis, without a tumor biopsy. In six patients with metastatic melanoma, breast, head and neck, or colorectal cancer, ctDNA analysis identified 63.25% to 97.4% of the neoantigens found by standard tumor tissue analysis, plus neoantigens tissue analysis missed. In a separate cohort of 69 patients with metastatic solid tumors, ctDNA was detectable in 32 (46.4%), and in 14 of 17 colorectal cancer patients (82.4%).
Metastatic competence in primary cutaneous melanoma is marked by somatic copy-number alterations and chromosomal instability rather than oncogenic point mutations, which were largely shared between primaries and metastases. Sequencing of 247 stage I/II primary melanomas and 60 matched metastases with median followup of 92 months yielded OncoCycle, a six-gene copy-number signature that predicted relapse independently of clinicopathological features. Matched pairs showed progression driven by continued copy-number evolution, with both monoclonal and polyclonal seeding resolved by clonal reconstruction.
BRCA1/2 loss is linked to a PKM1-dominant glycolytic state with elevated pyruvate kinase activity, found across 10,619 TCGA tumors and isogenic BRCA1/2-deficient models. PKM activation with small-molecule activators, including the FDA-approved mitapivat, triggered superoxide accumulation, disrupted PINK1-dependent mitochondrial quality control, induced DNA damage, and selectively killed BRCA2-deficient tumors in vivo while sparing BRCA2-proficient counterparts. The work recasts homologous recombination deficiency as a metabolic state and identifies PKM activation as a candidate therapy for HR-deficient cancers.
SMYD3 PROTACs, unlike catalytic inhibitors that lack phenotypic efficacy, degrade SMYD3 and curb proliferation and invasion in HPV-negative HNSCC cell lines. The compound IAP-08 degrades SMYD3 with a DC50 of about 177 nM and Dmax of about 90%, forms ternary complexes with XIAP E3 ligase, and shows favorable pharmacokinetics in vivo. Degradation, but not enzymatic inhibition, reprograms cell cycle, EMT and type I IFN response genes, supporting clinical development of IAP-08 in a disease where SMYD3 is overexpressed in about 60% of tumors.
The splicing co-factor SON suppresses circular RNA biogenesis in glioblastoma, and its elevation in radiation-resistant GBM is linked to widespread circRNA loss. SON knockdown raised circRNA abundance and attenuated PKR/NFκB signaling, and overexpression of the SON-suppressed circUSP1 and circSUCO reduced PKR activation and selectively decreased clonogenic survival after irradiation in radiation-resistant cells, with little effect on parental cells. The work defines a SON/circRNA/PKR pathway and points to PKR-inhibitory circRNAs as tools to resensitize resistant GBM to radiotherapy.
Single-cell ATAC-seq of 33 primary tumors and 7 metastases from 39 PDAC patients, paired with 10 single-cell RNA-seq profiles, maps the cis-regulatory landscape underlying malignant cell state plasticity. GATA6+/KRT17+ co-accessibility marks a classical-basal subtype-intermediate progenitor state (SIP) with limited epigenetic reprogramming and better clinical outcomes. Classical tumors repressing basal accessibility activate neural-like progenitor and tuft lineage enhancers, while basal committed tumors show esophageal transdifferentiation, both with poorer outcomes and distinct immune and stromal phenotypes.
Inhibition of the Werner syndrome helicase (WRN) enzyme exploits a new synthetic lethal vulnerability in cancers with microsatellite instability, a phase 1 trial shows. The approach offers a new way to target these tumors beyond immune checkpoint inhibition. No efficacy numbers are reported in the material.
The interstrand crosslinking agent KL-50 retains antiproliferative activity against MMR-deficient IDHmut glioma models, where temozolomide GI values rose 2.2- to 30.4-fold, and extends median survival in BT142 orthotopic xenografts from 107.5 to 194 days. KL-50 plus the HDAC inhibitor belinostat shows synergistic cytotoxicity in BT142, 905, and TS603 cultures, with CRISPR screening implicating PKMYT1 as a determinant of sensitivity. The work offers a preclinical route past MMR-associated TMZ resistance.
RO7589831, a first-in-class inhibitor of the synthetic lethal target Werner syndrome helicase, showed some partial responses in the dose-escalation stage of a phase 1 trial in patients with microsatellite instability and/or DNA mismatch repair-deficient solid tumors. The maximum tolerated dose was not reached.
Prolonged low-dose doxorubicin pushes mesenchymal-like MDA-MB-231 breast cancer cells toward an epithelial-like state, raising Caveolin-1 and E-cadherin protein levels and producing a compact morphology with more cell-cell contacts. The drug also shifted the lipid-anchored GFP-tH probe from the plasma membrane to the cytoplasm and altered autophagy markers, with decreased LC3-I and increased LC3-II, ATG5, and p62, consistent with autophagosome accumulation and impaired autophagic flux. The work links Ras membrane association and autophagy to phenotypic reprogramming under sub-cytotoxic doxorubicin.
Merck & Co. has licensed global rights to SPR2015, a preclinical KRAS G12D molecular glue inhibitor from China-based SciBrunch, paying $400 million up front. The deal follows reported failed M&A negotiations with Revolution Medicines in the $30 billion range, after that company reported in April that daraxonrasib led to a survival benefit in pancreatic cancer patients. Further deal terms for the SciBrunch agreement were not disclosed.
Microbial metabolites, not just gut bacterial composition, determine whether CAR T-cell therapy succeeds: in a cohort of 129 patients across three German university hospitals, specific metabolites correlated with response or failure. Low pre-treatment valerate predicted higher risk of disease progression, while indole-3-carboxaldehyde and indole-3-acetic acid were linked to unfavorable outcomes and reduced CAR T-cell efficacy in human and mouse models. A metabolite-based risk score predicted clinical response, and the team is preparing the CARBiome trial of microbiota transfer in multiple myeloma patients.
Merck has licensed exclusive global rights to SciBrunch Therapeutics' preclinical oral KRAS G12D (ON) inhibitor SPR2015, paying $400 million upfront with milestone payments that could bring the total to $2.13 billion. The deal has closed, and Merck recorded a pre-tax charge of $400 million, about 13 cents per share, in Q3. SciBrunch expects SPR2015 to enter human trials by the end of this year. The same day, Merck and Daiichi Sankyo withdrew an accelerated approval request for ifinatamab deruxtecan in extensive-stage small cell lung cancer after the FDA said the data did not support the filing.
Merck & Co. and Daiichi Sankyo withdrew their U.S. application for accelerated approval of ifinatamab deruxtecan, or I-DXd, in extensive-stage small-cell lung cancer after the FDA indicated Phase 2 response rate data were insufficient; a decision had been expected by Oct. 10. The B7-H3-targeting drug is still being tested against chemotherapy in relapsed disease, a trial in which recruitment was temporarily halted last year after higher than anticipated deaths from a serious lung condition. Competing B7-H3 drugs licensed to GSK (riz-rez) and Roche (tam-peli) have advanced, and I-DXd is also in Phase 3 testing in prostate cancer and esophageal squamous cell carcinoma.
Chinese drug developer Sipurui has granted Merck exclusive worldwide rights to develop, manufacture and commercialize SPR2015, an investigational oral KRAS G12D (ON) inhibitor. Sipurui receives an upfront payment of $400 million and is eligible for development, commercialization and other milestone payments tied to multiple indications, bringing the deal's total potential value to up to $2.13 billion.
The US FDA has approved belzutifan combined with lenvatinib, from Merck and Eisai, for adults with advanced clear cell renal cell carcinoma previously treated with a PD-1/PD-L1 inhibitor. The companies say it is the first approved regimen pairing a HIF-2α inhibitor with a multi-target VEGFR-TKI in this setting. Belzutifan, developed by Merck, was the first approved HIF-2α inhibitor and blocks the HIF-2α signalling pathway.
SciBrunch Therapeutics (Shanghai) has granted Merck Sharp & Dohme a global exclusive licence for SPR2015, a preclinical oral KRAS G12D(ON) inhibitor. SciBrunch will receive $400 million upfront and is eligible for milestone payments tied to development, commercialisation and other activities across multiple indications. The company focuses on RAS-pathway therapies for pancreatic, colorectal and lung cancers.
Ivonescimab extended median overall survival to 30.8 months versus 22.6 months for pembrolizumab in first-line treatment of PD-L1-positive (TPS ≥1%) advanced non-small cell lung cancer, cutting the risk of death by 27%. Data presented by Caicun Zhou of Shanghai East Hospital at the 2024 WCLC make ivonescimab the first drug to beat pembrolizumab head-to-head in a phase 3 trial with positive results on both progression-free and overall survival.
The European Commission's Directorate-General for Health and Food Safety has withdrawn the EU marketing authorisation for Hansoh Pharmaceutical's aumolertinib tablets, marketed overseas as Aumseqa. The decision, dated September 25, concerns the use of osimertinib clinical data in the marketing application. The drug had been approved on February 12, 2026, less than eight months earlier, and Hansoh says it will resubmit the application as soon as possible.
