Our findings demonstrate that FTIs Lonafarnib and Tipifarnib impair MVM, highlighting the essential role of farnesylation in biomineralization.

The hub gene CCND1 and its targeting drug candidate Tipifarnib may contribute to PTC treatment.

Lamins have also been shown to be dysregulated in a multitude of cancers, and research has uncovered a diabolical role of lamins in oncogenesis. The understanding of laminopathies and dysregulation of lamins resulting in disorders is critical in developing novel therapeutic strategies through drug repurposing and epigenetic modulation to curb the burden of the diseases.

The farnesyltransferase inhibitor tipifarnib blocked mutant HRAS-PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cells, whereas KRASG12C inhibitors blocked mutant KRAS-MEK signaling and synergized with PI3K inhibitors in KRASG12C-mutated cells. Synergy was abolished in MEFs lacking all RAS proteins and in cancer cell lines in which nonmutated RAS family members were deleted. Our data highlight the critical role of wild-type RAS family members in supporting mutant RAS signaling and its importance as a therapeutic cotarget in RAS-mutated cancers.

P1/2, N=40, Active, not recruiting, Kura Oncology, Inc. | Trial completion date: Jul 2025 --> Dec 2025 | Trial primary completion date: Jul 2025 --> Dec 2025

The improved knowledge of the HDV life cycle has led to the development and approval of the first HDV-direct antiviral, Bulevirtide (BLV)...Despite recent advances in antiviral treatment, strategies to achieve HBsAg loss, which most closely resembles HDV cure, are not available and antiviral treatment for patients with advanced liver disease is limited. The third international Delta Cure meeting, held in Milan in October 2024, aimed to share the latest findings, and this review highlights key takeaways from the lectures and research on HDV.

HRAS knockdown with siRNA suppressed the in vitro migration ability of HRAS mutation-positive cells but not that of HRAS mutation-negative cells. In conclusion, a positive HRAS mutation could be an indicator of distant metastasis and poor prognosis, as well as a potential therapeutic target.

P1/2, N=40, Active, not recruiting, Kura Oncology, Inc. | Recruiting --> Active, not recruiting

These findings underscore the critical role of antitumor immunity, particularly CD8+T cell activity, in the efficacy of tipifarnib alone and in combination with alpelisib. The triple combination of tipifarnib, alpelisib, and anti-PD1 treatment showed superior antitumor activity and extended survival in preclinical models, suggesting its potential as a therapeutic strategy for HNSCC patients with HRAS- and PIK3CA-mutation.

In this study, we created stable doxycycline inducible cell lines overexpressing HRAS G12 mutants in MC3T3-E1 preosteoblast cell line and analyzed their impact on osteoblast differentiation. At the molecular level, Tipifarnib was not able to block HRAS activation, but impaired HRAS localization to the plasma membrane, and inhibited MAPK activation and Opn expression. Thus, HRAS abundance/activation and its potential crosstalk with OPN may be more critical for osteogenic differentiation than previously assumed.

Additionally, we identified a synergistic drug combination involving tipifarnib and a ferroptosis inducer and discovered PTP4A1 as a regulator of interferon signaling. Our data, covering 15,080 proteins, offer valuable insights for future studies of farnesylation and FTIs.

P1/2, N=40, Recruiting, Kura Oncology, Inc. | Trial completion date: Sep 2024 --> Jul 2025 | Trial primary completion date: Sep 2024 --> Jul 2025