Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers.

KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line-derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers.

KRASG12C inhibitors have revolutionized the treatment landscape for cancer patients harboring the G12C mutant isoform of KRAS. With the recent FDA approval of sotorasib and adagrasib, patients now have access to more promising treatment options. However, patients who receive these agents as a monotherapy usually develop drug resistance. Thus, there is a need to develop logical combination strategies that can delay or prevent the onset of resistance and simultaneously enhance the antitumor effectiveness of the treatment regimen. In this study, we aimed at pharmacologically targeting PAK4 by KPT9274 in combination with KRASG12C inhibitors in KRASG12C mutant pancreatic ductal adenocarcinoma (PDAC) and nonâ€"small cell lung cancer (NSCLC) preclinical models. PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We assessed the cytotoxicity of PAK4 and KRASG12C inhibitors combination in KRASG12C mutant 2D and 3D cellular models. KPT9274 synergized with both sotorasib and adagrasib in inhibiting the growth of KRASG12C mutant cancer cells. The combination was able to reduce the clonogenic potential of KRASG12C mutant PDAC cells. We also evaluated the antitumor activity of the combination in a KRASG12C mutant PDAC cell line-derived xenograft (CDX) model. Oral administration of a sub-optimal dose of KPT9274 in combination with sotorasib (at one-fourth of MTD) demonstrated significant inhibition of the tumor burden ( p = 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model where KPT9274, acting as an adjuvant, prevented tumor relapse following the discontinuation of sotorasib treatment ( p = 0.0001). KPT9274 and sotorasib combination also resulted in enhanced survival. This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitor KPT9274 both in vitro and in vivo resulting in remarkably enhanced antitumor activity and survival outcomes. Significance: KRASG12C inhibitors demonstrate limited durable response in patients with KRASG12C mutations. In this study, combining PAK4 inhibitor KPT9274 with KRASG12C inhibitors has resulted in potent antitumor effects in preclinical cancer models of PDAC and NSCLC. Our results bring forward a novel combination therapy for cancer patients that do not respond or develop resistance to KRASG12C inhibitor treatment.

Delivery of Interleukin-4-Encoding Lentivirus Using Multiple-Channel Bridges Enhances Nerve Regeneration.

OBJECTIVES/HYPOTHESIS: Facial nerve injury is a source of major morbidity. This study investigated the neuroregenerative effects of inducing an anti-inflammatory environment when reconstructing a facial nerve defect with a multichannel bridge containing interleukin-4 (IL-4)-encoding lentivirus. STUDY DESIGN: Animal study. METHODS: Eighteen adult Sprague-Dawley rats were divided into three groups, all of which sustained a facial nerve gap defect. Group I had reconstruction performed via an IL-4 multichannel bridge, group II had a multichannel bridge with saline placed, and group III had no reconstruction. RESULTS: Quantitative histomorphometric data were assessed 10 weeks after injury. On post hoc analysis, the IL-4 bridge group demonstrated superior regeneration compared to bridge alone on fiber density (mean = 2,380 ± 297 vs. 1,680 ± 441 fibers/mm2 , P = .05) and latency time (mean = 2.9 ms ± 0.6 ms vs. 3.6 ms ± 0.3 ms, P < .001). There was significantly greater regeneration in the IL-4 bridge group versus unreconstructed defect for total fiber and density measurements (P ≤ .05). Comparison of facial motor-evoked distal latencies between the IL-4 bridge group versus bridge alone revealed significant electrophysiological improvement at week 8 (P = .02). CONCLUSIONS: Inflammation has been implicated in a variety of otolaryngologic disorders. This study demonstrates that placement of a multichannel bridge with lentivirus encoding IL-4 improves regenerative outcomes following facial nerve gap injury in rodents. This effect is likely mediated by promotion of an anti-inflammatory environment, and these findings may inform future therapeutic approaches to facial nerve injury. LEVEL OF EVIDENCE: NA Laryngoscope, 2020.

Effect of Motor versus Sensory Nerve Autografts on Regeneration and Functional Outcomes of Rat Facial Nerve Reconstruction.

Cranial nerve injury is disabling for patients, and facial nerve injury is particularly debilitating due to combined functional impairment and disfigurement. The most widely accepted approaches for reconstructing nerve gap injuries involve using sensory nerve grafts to bridge the nerve defect. Prior work on preferential motor reinnervation suggests, however, that motor pathways may preferentially support motoneuron regeneration after nerve injury. The effect of motor versus sensory nerve grafting after facial nerve injury has not been previously investigated. Insights into outcomes of motor versus sensory grafting may improve understanding and clinical treatment of facial nerve paralysis, mitigating facial asymmetry, aberrant reinnervation, and synkinesis. This study examined motor versus sensory grafting of the facial nerve to investigate effect of pathway on regeneration across a 5-mm rodent facial nerve defect. We enrolled 18 rats in 3 cohorts (motor, sensory, and defect) and recorded outcome measures including fiber count/nerve density, muscle endplate reinnervation, compound muscle action potential, and functional whisker twitch analysis. Outcomes were similar for motor versus sensory groups, suggesting similar ability of sensory and motor grafts to support regeneration in a clinically relevant model of facial nerve injury.