Zarnestra (tipifarnib)

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

Furthermore, our study showed that aberrant methylation of HTR7 was associated with the infiltration of many immune cells, including Th1, Th17, DC, macrophages, etc. In cancer pathways, HTR7 could inhibit the cell cycle, DNA damage, and hormone AR pathways and activate the EMT and RAS/MAPK pathways. GO and KEGG enrichment analyses revealed that HTR7 could participate in the G protein-coupled receptor signaling pathway, serotonin receptor signaling pathway, hormone signaling, cAMP signaling pathway, etc. Several drugs, including 5-fluorouracil, gemcitabine, sunitinib, tipifarnib, and trametinib, may be sensitive to high HTR7 expression in tumors.

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

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.

Risk prediction models based on multi-omics data and machine learning algorithms provide potential reference targets for prognosis prediction and personalised treatment of cervical cancer patients. The results of this study provide important insights into the understanding of the health risks of cervical cancer associated with Benzo[a]pyrene and Nicotine exposures and the development of preventive and therapeutic strategies for cervical cancer, which may contribute to the development of precision medicine for cervical cancer.

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

P2, N=1376, Active, not recruiting, National Cancer Institute (NCI) | N=2316 --> 1376 | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Jun 2025 --> Mar 2025

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.