Skin Deep: A Fascinating Case Report of Immunotherapy-Triggered, Treatment-Refractory Autoimmune Lichen Planus and Keratoacanthoma.

This case discusses a 62-year-old woman with de novo metastatic lung adenocarcinoma (PD-L1 >50% with a KRAS G12C mutation, ALK and EGFR negative) who was on pembrolizumab for 1 year without any significant toxicity, only low-grade dermatitis and hypothyroidism. She was transitioned to pembrolizumab every 6 weeks at 4 mg/kg and began to develop oral sores shortly thereafter. The sores proved refractory to nystatin and mouth rinses containing corticosteroids, and the patient was ultimately diagnosed with autoimmune-triggered lichen planus. Unfortunately, her symptoms also proved refractory to typical treatments for lichen planus and worsened to the point where she began to develop cutaneous lesions and difficulty swallowing. Unfortunately, she also developed a keratoacanthoma that required excision. The pembrolizumab was stopped, and the patient's symptoms improved with 5 days of systemic prednisone, metronidazole, and triamcinolone oral paste. Her NSCLC remains stable off active treatment for 6 months. This case study is on rare auto-immune toxicity as well as a keratoacanthoma from anti-PD-(L) 1 blockade, accompanied by sustained treatment response after cessation of the offending drug.

FBXO31 protects against genomic instability by capping FOXM1 levels at the G2/M transition.

F-box proteins in conjunction with Skp1, Cul1 and Rbx1 generate SCF complexes that are responsible for the ubiquitination of proteins, leading to their activation or degradation. Here we show that the F-box protein FBXO31 is required for normal mitotic progression and genome stability due to its role in regulating FOXM1 levels during the G2/M transition. FBXO31-depleted cells undergo a transient delay in mitosis due to an activated spindle checkpoint concomitant with an increase in lagging chromosomes and anaphase bridges. FBXO31 regulates mitosis in part by controlling the levels of FOXM1, a transcription factor and master regulator of mitosis. FBXO31 specifically interacts with FOXM1 during the G2/M transition, resulting in FOXM1 ubiquitination and degradation. FBXO31 depletion results in increased expression of FOXM1 transcriptional targets and mimics the FOXM1 overexpression. In contrast, co-depletion of FBXO31 and FOXM1 restores the genomic instability phenotype but not the delay in mitosis, indicating that FBXO31 probably has additional mitotic substrates. Thus, FBXO31 is the first described negative regulator of FOXM1 during the G2/M transition.

Centrobin regulates the assembly of functional mitotic spindles.

The proper function of the spindle is crucial to the high fidelity of chromosome segregation and is indispensable for tumor suppression in humans. Centrobin is a recently identified centrosomal protein that has a role in stabilizing the microtubule structure. Here we functionally characterize the defects in centrosome integrity and spindle assembly in Centrobin-depleted cells. Centrobin-depleted cells show a range of spindle abnormalities including unfocused poles that are not associated with centrosomes, S-shaped spindles and mini spindles. These cells undergo mitotic arrest and subsequently often die by apoptosis, as determined by live cell imaging. Co-depletion of Mad2 relieves the mitotic arrest, indicating that cells arrest due to a failure to silence the spindle checkpoint in metaphase. Consistent with this, Centrobin-depleted metaphase cells stained positive for BubR1 and BubR1 S676. Staining with a panel of centrosome markers showed a loss of centrosome anchoring to the mitotic spindle. Furthermore, these cells show less cold-stable microtubules and a shorter distance between kinetochore pairs. These results show a requirement of Centrobin in maintaining centrosome integrity, which in turn promotes anchoring of mitotic spindle to the centrosomes. Furthermore, this anchoring is required for the stability of microtubule-kinetochore attachments and biogenesis of tension-ridden and properly functioning mitotic spindle.