Huy Nguyen

Rhabdoid tumors (RTs) are highly aggressive cancers driven by biallelic mutation of SMARCB1 , a core subunit of the BAF (SWI/SNF) complex. We found that SMARCB1 -deficient tumors have a defect in the microhomology-mediated end joining (MMEJ) pathway, and SMARCB1 is essential for maintaining the protein level of the core MMEJ protein, DNA Polymerase theta (PolΘ). Mechanistically, SMARCB1 facilitates the nuclear export of the POLQ mRNA through its interaction with the nuclear pore complex. Interestingly, loss of MMEJ in RT cells leads to a compensatory activation of, and a hyper-dependence on, the Fanconi Anemia (FA)/BRCA pathway. Notably, degraders of RBM39, a splicing modulator, show strong antitumor efficacy in RT models in vitro and in vivo by disrupting FA/BRCA pathway. SMARCB1 and other cBAF/pBAF components are important for maintenance of MMEJ activity and PolΘ protein level, suggesting that BAF-deficient cancers more broadly may be treated by targeted inhibition of the FA/BRCA pathway.

Supplementary Figure S5. Chemical structures of USP1 inhibitors.

Purpose:PARP inhibition has demonstrated efficacy in patients with platinum-sensitive pancreatic cancer with germline BRCA1/2 pathogenic variants (PV). Whether PARP inhibitors might be effective in a broader population of patients with pancreatic cancer remains under investigation.Patients and Methods:This multicenter, open-label phase II trial (NCT03601923) enrolled patients with advanced pancreatic cancers who harbored germline or somatic BRCA1, BRCA2, PALB2, ATM, and/or CHEK2 PVs. Patients with prior progression on platinum-based therapy were excluded. Patients were treated with niraparib 200 or 300 mg once daily, with their initial dose determined by weight and platelet count. The primary endpoint was 6-month progression-free survival (PFS).Results:Thirty-two patients [10 women (31%); median age: 67 years] were enrolled. Patients had a PV in at least one of the following genes: ATM (n = 14), BRCA2 (n = 10), PALB2 (n = 3), CHEK2 (n = 4), or BRCA1 (n = 2). The 6-month PFS was 25% [90% confidence interval (CI), 13%–41%] for the overall population, exceeding the preestablished threshold of 17%. The median PFS for the entire population was 2 months (95% CI, 1.4–3.8), and the objective response rate was 14% (95% CI, 4%–33%). All six patients with ≥6 months of PFS and evaluable tumor zygosity had biallelic inactivation of a DNA repair gene. Three patients with biallelic inactivation of ATM and no progression on prior chemotherapy received niraparib for more than 1 year.Conclusions:Niraparib demonstrated clinically meaningful benefit in a subset of patients. The prolonged PFS observed in patients with biallelic ATM loss warrants further investigation.

Supplementary Figure S1: CONSORT diagram indicating patient disposition.

Supplementary Figure S6: Genomic characterization of BRCA2 reversion mutations

Supplementary Materials and Methods

CRISPR screen results in UWB1.289 cells treated with USP1 inhibitor versus DMSO

Supplementary Figure S2: Kaplan-Meier estimates of overall survival (OS) in patients treated with niraparib across the entire trial population

Supplementary Figure S4. USP1 inhibitor and a PARP inhibitor combination treatment is well tolerated in mice

Clinical characteristics of tumor samples used to generate patient derived organoids