SLFN11 (Schlafen Family Member 11)

Employing Micro-C, a micrococcal nuclease-based 3D genome mapping technique, we show that EZH1/2 inhibition with Valemetostat induced significant changes at multiple genome organizational levels (compartment, topological associated domain, and chromatin loop) without incurring cell death in NE SCLC...Notably, EZH1/2 inhibition reactivated Class I MHC expression by facilitating enhancer-promoter looping. Our results demonstrate that repression of a subset of EZH2 targets including Class I MHC genes is affected through modulation of 3D genome structure to the level of chromatin looping and further support clinical investigation of EZH2 inhibition in boosting therapeutic efficacy of ICI in SCLC patients.

P2, N=44, Recruiting, ETOP IBCSG Partners Foundation | Trial completion date: Jun 2026 --> Jun 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

Subsequently, targeting GPL biosynthesis (FSG67) restored DNA-damaging agent (SN-38) sensitivity in SLFN11-deficient EWS model, revealing a potential metabolic vulnerability to overcome chemoresistance. Furthermore, SLFN11 knockout tumors exhibited an elevated phosphocholine/glycerophosphocholine ratio, offering a potential non-invasive diagnostic biomarker.

ISL1 serves as both a predictive biomarker and functional dependency, as evidenced by essentiality for cell survival and loss following treatment. Prospective studies using ISL1 as a predictive biomarker for lurbinectedin are planned.

P2, N=103, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2025 --> Jan 2027

Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase-polymerase (PrimPol)-mediated repriming...Finally, we demonstrate that rapid RPA exhaustion on chemical inhibition of DNA polymerase α activates SLFN11-dependent cell death. Together, our results implicate RPA exhaustion as a general mechanism to activate SLFN11 in response to heightened replication stress.

In this real-world cohort, a subset of patients with recurrent ovarian cancer achieved durable, potentially curative responses with olaparib maintenance, regardless of their BRCA mutation status. When evaluating PARP inhibitor therapy, long-term progression-free survival should be considered a key endpoint.

TERT-negative osteosarcoma U2-OS (ALT) cells, that normally lack SLFN11 expression, show SLFN11 localization to telomeres upon doxycycline-induced SLFN11 expression...Furthermore, SLFN11 suppresses ALT induction in ATRX-depleted prostate carcinoma DU145 cells. Collectively, our findings identify SLFN11 as a negative telomeric regulator of the ALT pathway, indicating that its loss, together with ATRX/DAXX inactivation, contributes to ALT activation.

We evaluate detection methodologies, highlight the promise of dynamic monitoring via liquid biopsy, and explore rational combination therapies designed to leverage SLFN11 function. Finally, we provide a forward-looking perspective on integrating SLFN11 into biomarker-driven strategies and outline the clinical validation required to realize its full potential in precision oncology.

Furthermore, we demonstrate that combined inhibition of these factors with MSC778 induces synergistic killing of cancer cells. Together these data highlight FEN1 inhibition as an attractive precision oncology strategy either as monotherapy or as a combination therapy with a broad range of current and next generation DDR-targeting agents.

P2, N=23, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Nov 2026

To identify the most suitable PARPi for UC, we compared Olaparib with Talazoparib. In conclusion, we suggest Talazoparib treatment of UC to be highly efficacious on all models examined when combined with PLX51107. This new combination treatment allows efficient application of PARPi Talazoparib to all UC patients, independent of Cisplatin pretreatment and genetic BRCAness.