Biology subjects

Ganem, N.

Publications and source records attributed to Ganem, N..

2 recordsLinked to original sources

bioRxiv2026

KIF18A Inhibition as a Therapeutic Strategy in Cancers with Rb Pathway Inactivation

KIF18A inhibition has emerged as a therapeutic strategy for chromosomally unstable cancers, but clinical development is limited by the absence of a deployable predictive biomarker. Here we identify strong, diffuse p16INK4a expression, a well-established surrogate marker of Rb-pathway inactivation, as a predictive biomarker of response to KIF18A inhibition, and show that Rb-pathway inactivation marks a biologically distinct subset of cancers sensitive to this therapeutic approach. In sensitive models, low Rb activity is associated with robust spindle assembly checkpoint signaling and prolonged mitotic arrest following KIF18A inhibition. Weakening the spindle assembly checkpoint in this context is sufficient to confer resistance. Across three independent pan-cancer sensitivity datasets generated with distinct KIF18A inhibitors, Rb-pathway altered models were significantly more sensitive than histology-matched Rb-intact comparators, with the strongest association observed in cancers harboring direct RB1 loss or inactivating mutation. Guided by this mechanism, we retrospectively analyzed p16INK4a expression by immunohistochemistry (IHC) in pre-treatment tumor biopsies from 79 heavily pre-treated high-grade serous ovarian cancer patients across three dose-escalation or expansion cohorts and treated with two different KIF18A inhibitors (sovilnesib and VLS-1488) sharing a common mechanism of action. p16INK4a-high tumors showed substantially higher objective response rates than their p16INK4a-low counterparts (36.0% versus 2.2%; P = 0.0002) and markedly longer progression-free survival (median 24.3 versus 7.9 weeks; hazard ratio, 0.16; P < 0.0001). These findings establish p16INK4a as a mechanistically-based, clinically implementable biomarker of clinical response to KIF18A inhibition that is poised to support pan-cancer development of KIF18A inhibitors guided by Rb-pathway inactivation.

cancer biology↗

bioRxiv2017

Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have now found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma, express an active DNA transposase PGBD5 that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we found that mouse and human cells deficient in non-homologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce hypersensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment, and underwent apoptosis in both dividing and G1 phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against the majority of neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdoid tumor cells tested, while sparing non-transformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including significant anti-tumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.

cancer biology↗