PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non-small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members.     

Melanocytic Nevi in Children of Southern Italy: Dermoscopic,Constitutional, and Environmental Factors

The objective was to estimate the prevalence of melanocytic nevi (MN) in children and to determine their dermoscopic characteristics and relationship with anatomic location and environmental and constitutional factors. The population was a randomly selected sample of 144 children who attended primary schools in Naples, Italy. Before physical examination of the children, standardized interviews were conducted with their parents. Follow‐up interviews of both the children and parents were conducted 1 year later. Photographic and dermoscopic images were obtained. Boys had more MN than girls; 465 MN (55.6%) were observed in boys and 371 (44.4%) in girls (p < 0.05). The trunk and neck were the most common locations of MN (p < 0.001). The main dermoscopic feature of all MN observed was a globular pattern (p < 0.001). A significant correlation between duration of sunbathing and MN counts was revealed (p < 0.05). At 1‐year follow‐up, 118 new MN were identified in 66 children. The trunk and neck areas were the most common regions involved in the appearance of new MN (n = 68, 57.6% of all new MN, p < 0.001). The new MN count was significantly higher in children who reported more sunbathing (p < 0.001). Changes in the dermoscopic pattern were observed in 45 persistent MN, demonstrating more MN with a reticular‐globular pattern, especially on the trunk, neck, and upper extremities (p < 0.001). MN development in early life is the result of complicated relationships between nevus evolution, anatomic location, and environmental and constitutional factors.     

Mitochondrial dysfunction in affected skin and increased mitochondrial DNA in serum from patients with psoriasis

Psoriasis is characterized by keratinocyte proliferation and chronic inflammation, but the pathogenesis is still unclear. Dysregulated mitochondria (mt) could lead to reduced apoptosis and extracellular secretion of mtDNA, acting as “innate pathogen” triggering inflammation. Serum was obtained from healthy volunteers and psoriatic patients. Mitochondrial DNA was extracted from the serum and amplified with quantitative PCR (qPCR). Punch biopsies were obtained from lesional and non‐lesional psoriatic skin (10 cm apart) and from healthy volunteers, were placed in RNA later and were stored at ?80°C until RNA was extracted and cDNA was synthesized; gene expression of uncoupling protein 2 (UCP2), Dynamin‐related protein 1 (Drp1) and calcineurin, involved in the regulation of mitochondria function, was detected with qPCR. Mitochondrial DNA was significantly increased (7s, P = 0.0496 and Cytochrome B, CytB, P = 0.0403) in the serum of psoriatic patients (n = 63) as compared to controls (n = 27). Gene expression was significantly reduced for UCP2 (P = 0.0218), Drp1 (P = 0.0001) and calcineurin (P = 0.0001) in lesional psoriatic skin, as compared to non‐lesional or control skin. Increased serum extracellular mtDNA in psoriatic patients and decreased expression of mitochondrial regulatory proteins in psoriatic skin suggest increased inflammation and reduced keratinocyte apoptosis, respectively. Inhibitors of mtDNA secretion and/or UCP2 stimulants may be potential treatment options.