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Volume 2 Issue 6, June 2021
News & Views
FTO, an m6A RNA demethylase, is known mainly as an oncoprotein in various cancer types. FTO is now shown to act as a cancer suppressor in a subset of epithelial tumors through an interplay between epithelial-to-mesenchymal transition and Wnt signaling.
The DNA polymerase Polθ is synthetic lethal with homologous-recombination deficiency, but a lack of specific targeting compounds has limited its therapeutic potential. Two studies now describe first-in-class inhibitors of Polθ with in vivo efficacy and thus provide alternative therapeutic approaches to PARP inhibitors for cancers deficient in homologous recombination.
Cancer in Translation
Despite substantial advances in understanding of the molecular features of gliomas, the therapeutic options for these aggressive tumors remain scarce. Rich, Mitchell and colleagues provide their views about a phase 1 clinical trial testing the safety and efficacy of vaccines against cancer expressing mutant metabolic enzyme IDH1 in patients with high-grade glioma.
Scatiltri and colleagues review the paradigms of targeting PI3K in solid tumors in the clinic, including the progress so far in developing effective inhibitors as well as clinical limitations due to toxicity and therapeutic resistance.
A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors
D’Andrea and colleagues identify the antibiotic novobiocin as a specific POLQ inhibitor with preclinical activity in homologous-recombination-deficient breast and ovarian tumors in vivo, including these with acquired PARP inhibitor resistance.
Downregulation of the FTO m6A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors
Fuks and colleagues report that downregulation of the FTO m6A RNA demethylase activates the Wnt pathway, promoting EMT-mediated progression of epithelial tumors and conferring sensitivity to Wnt inhibitors.
Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients
Amrolia and colleagues characterize the clonal origins of long-term persistent CAR T cells from the CARPALL trial using low-affinity CAR T cells mediating long-term anti-leukemic control in patients through TSCM-mediated responses.
A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage
Nik-Zainal and colleagues leverage CRISPR–Cas9 and whole-genome sequencing to examine mutational patterns following knockout of 42 human DNA repair genes. They further develop and validate a clinically relevant tool to detect mismatch repair-deficient tumors.
Serial single-cell genomics reveals convergent subclonal evolution of resistance as patients with early-stage breast cancer progress on endocrine plus CDK4/6 therapy
Bild and colleagues identify convergent clonal evolution mechanisms through single-cell genomic analyses, explaining therapy resistance in patients with early-stage breast cancer treated with endocrine and CDK4/6 therapy in the FELINE trial.