Baricitinib, a JAK-STAT Inhibitor, Reduces the Cellular Toxicity of the Farnesyltransferase Inhibitor Lonafarnib in Progeria Cells

Hutchinson–Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called “progerin” that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.

Mislocalization and clearance of neuronal Rhes as a novel hallmark of tauopathies

ABSTRACTThe farnesyltransferase inhibitor lonafarnib reduces tau inclusion burden and atrophy in familial tauopathy models by inhibiting farnesylation on the Ras GTPase, Rhes, and activating autophagy. While hinting at a role of Rhes in tau aggregation, it is unclear how translatable these results are for sporadic forms of tauopathy. We used a combination of quantitative pathology using multiplex immunofluorescence for Rhes, several tau post-translational modifications, and single nucleus RNA sequence analysis to interrogate Rhes presence and distribution in human cortical neurons and Rhes relation to tau and TDP-43 changes. snRNA data suggest that Rhes is found in all cortical neuron subpopulations, not only in striatum cells. Histologic investigation in hippocampal formation from multiple postmortem cases in five different tauopathies and healthy controls and TDP-43 proteinopathy showed that nearly all neurons in control brains display a pattern of diffuse cytoplasmic Rhes positivity. However, in the presence of abnormal tau, but not TDP-43 inclusions, the patterns of neuronal cytoplasmic Rhes tend to present as either punctiform or fully absent. Our findings reinforce the relevance of the link between Rhes changes and tau pathology suggested by in vivo and in vitro models of tauopathy and support a potential clinical application of lonafarnib to tauopathies.

Tipifarnib, a farnesyltransferase inhibitor, for metastatic urothelial carcinoma harboring HRAS mutations.

5086 Background: Tipifarnib is a farnesyltransferase inhibitor known to block RAS signaling and attenuate cancer cell proliferation. We tested the activity and safety of tipifarnib in patients with previously treated urothelial carcinoma (UC) carrying HRAS mutations. Methods: In a prospective phase II clinical trial, genetic screening was performed in 224 UC patients; those with missense HRAS mutations or STK11:rs2075606 received study treatment. Eligible patients received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-d treatment cycles. The primary endpoint was progression-free survival at 6 mo (PFS6). With two-stage design, at least 18 patients were required. Results: Among the 224 patients screened, we found 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11: rs2075606 carriers. In 21 patients enrolled, 14 and 7 patients had HRAS mutations and STK11:rs2075606, respectively. The most frequent adverse events included fatigue and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as a STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. Response rate was 24% (4 missense and one nonsense frameshift HRAS mutation); no response observed in UC patients with wild type HRAS tumors. Conclusions: Oral tipifarnib showed a manageable safety profile and encouraging anti-tumor efficacy against treatment-refractory UC containing HRAS mutations. Clinical trial information: NCT02535650 .