The Molecular Context of Vulnerability for CDK9 Suppression in Triple Wild-Type Melanoma.

Approximately half of melanoma tumors lack a druggable target and are unresponsive to current targeted therapeutics. One proposed approach for treating these therapeutically orphaned tumors is by targeting transcriptional dependencies (oncogene starvation), whereby survival factors are depleted through inhibition of transcriptional regulators. A drug screen identified a CDK9 inhibitor (SNS-032) to have therapeutic selectivity against wild-type (wt) BRAFwt/NRASwt melanomas compared with BRAFmut/NRASmut mutated melanomas. We then used two strategies to inhibit CDK9 in vitro-a CDK9 degrader (TS-032) and a selective CDK9 kinase inhibitor (NVP-2). At 500 nM, both TS-032 and NVP-2 demonstrated greater suppression of BRAFwt/NRASwt/NF1wt cutaneous and uveal melanomas than mutant melanomas. RNA sequencing analysis of eight melanoma lines with NVP-2 treatment demonstrated that the context of this vulnerability appears to converge on a cell cycle network that includes many transcriptional regulators, such as the E2F family members. The Cancer Genome Atlas human melanoma tumor data further supported a potential oncogenic role for E2F1 and E2F2 in BRAFwt/NRASwt/NF1wt tumors and a direct link to CDK9. Our results suggest that transcriptional blockade through selective targeting of CDK9 is an effective method of suppressing therapeutically orphaned BRAF/NRAS/NF1 wt melanomas.

Loss of ACK1 Upregulates EGFR and Mediates Resistance to BRAF Inhibition.

Targeted BRAF(V600E) suppression by selective BRAF inhibitors (BRAFis; e.g., vemurafenib and dabrafenib) has led to a sea change in the treatment of metastatic melanoma. Despite frequent upfront responses, acquired resistance has compromised long-term applicability. Among the various mechanisms of resistance, activation of multiple receptor tyrosine kinases is a known critical factor that contributes to vemurafenib resistance⁠. EGFR activation has been recurrently identified in a set of vemurafenib-resistant melanomas, but little is known about how EGFR, or possibly other receptor tyrosine kinases, becomes activated. Here, we report that ACK1, a protein kinase that modulates EGFR turnover, is downregulated in vemurafenib-resistant melanoma cells. We also found that ACK1 depletion with short hairpin RNA decreased EGFR degradation when activated by epidermal growth factor, increased EGFR protein expression, and conferred resistance to BRAFis both in vitro and in vivo. Vemurafenib resistance mediated by ACK1 inhibition can be reversed by the EGFR inhibitor gefitinib. Our data indicate that ACK1 loss may be a post-transcriptional mechanism that increases EGFR signaling and contributes to drug resistance.

Cancer risks associated with the germline MITF(E318K) variant.

The MITF(E318K) variant confers moderate risk for cutaneous melanoma. While there are small studies suggesting that this risk is associated with other malignancies (e.g. renal cell carcinoma), little is known about the role of this variant in specifying risk for other cancers. In this study, we perform a systematic review and meta-analysis of the published data as a backdrop to a whole-exome sequence(WES)-based characterization of MITF(E318K) risk for various cancers in sporadic samples from the TCGA and several genetically-enriched patient cohorts. We found minimal evidence of MITF(E318K)'s contribution to non-melanoma cancer risk among individuals with low inherited risks of melanoma (OR 1.168; 95% CI 0.78-1.74; p = 0.454), suggesting that earlier reports of an association between this variant and other malignancies may be related to shared environmental or polygenic risk factors rather than MITF(E318K). Interestingly, an association was observed with uterine carcinosarcoma, (OR 9.24; 95% CI 2.08-37.17; p = 0.024), which was not previously described. While more research needs to be completed, this study will help update cancer screening recommendations for patients with the MITF(E318K) variant.

KIT and Melanoma: Biological Insights and Clinical Implications.

Melanoma, originating from epidermal melanocytes, is a heterogeneous disease that has the highest mortality rate among all types of skin cancers. Numerous studies have revealed the cause of this cancer as related to various somatic driver mutations, including alterations in KIT-a proto-oncogene encoding for a transmembrane receptor tyrosine kinase. Although accounting for only 3% of all melanomas, mutations in c-KIT are mostly derived from acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, inhibition of c-KIT has been exploited for clinical trials in advanced melanoma. Here, apart from the molecular background of c-KIT and its cellular functions, we will review the wide distribution of alterations in KIT with a catalogue of more than 40 mutations reported in various articles and case studies. Additionally, we will summarize the association of KIT mutations with clinicopathologic features (age, sex, melanoma subtypes, anatomic location, etc.), and the differences of mutation rate among subgroups. Finally, several therapeutic trials of c-KIT inhibitors, including imatinib, dasatinib, nilotinib, and sunitinib, will be analyzed for their success rates and limitations in advanced melanoma treatment. These not only emphasize c-KIT as an attractive target for personalized melanoma therapy but also propose the requirement for additional investigational studies to develop novel therapeutic trials co-targeting c-KIT and other cytokines such as members of signaling pathways and immune systems.

Keratinocyte Carcinomas: Current Concepts and Future Research Priorities.

Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are keratinocyte carcinomas, the most frequently diagnosed cancers in fair-skinned populations. Ultraviolet radiation (UVR) is the main driving carcinogen for these tumors, but immunosuppression, pigmentary factors, and aging are also risk factors. Scientific discoveries have improved the understanding of the role of human papillomaviruses (HPV) in cSCC as well as the skin microbiome and a compromised immune system in the development of both cSCC and BCC. Genomic analyses have uncovered genetic risk variants, high-risk susceptibility genes, and somatic events that underlie common pathways important in keratinocyte carcinoma tumorigenesis and tumor characteristics that have enabled development of prediction models for early identification of high-risk individuals. Advances in chemoprevention in high-risk individuals and progress in targeted and immune-based treatment approaches have the potential to decrease the morbidity and mortality associated with these tumors. As the incidence and prevalence of keratinocyte carcinoma continue to increase, strategies for prevention, including effective sun-protective behavior, educational interventions, and reduction of tanning bed access and usage, are essential. Gaps in our knowledge requiring additional research to reduce the high morbidity and costs associated with keratinocyte carcinoma include better understanding of factors leading to more aggressive tumors, the roles of microbiome and HPV infection, prediction of response to therapies including immune checkpoint blockade, and how to tailor both prevention and treatment to individual risk factors and needs.

Comparative evidence for the independent evolution of hair and sweat gland traits in primates.

Humans differ in many respects from other primates, but perhaps no derived human feature is more striking than our naked skin. Long purported to be adaptive, humans' unique external appearance is characterized by changes in both the patterning of hair follicles and eccrine sweat glands, producing decreased hair cover and increased sweat gland density. Despite the conspicuousness of these features and their potential evolutionary importance, there is a lack of clarity regarding how they evolved within the primate lineage. We thus collected and quantified the density of hair follicles and eccrine sweat glands from five regions of the skin in three species of primates: macaque, chimpanzee and human. Although human hair cover is greatly attenuated relative to that of our close relatives, we find that humans have a chimpanzee-like hair density that is significantly lower than that of macaques. In contrast, eccrine gland density is on average 10-fold higher in humans compared to chimpanzees and macaques, whose density is strikingly similar. Our findings suggest that a decrease in hair density in the ancestors of humans and apes was followed by an increase in eccrine gland density and a reduction in fur cover in humans. This work answers long-standing questions about the traits that make human skin unique and substantiates a model in which the evolution of expanded eccrine gland density was exclusive to the human lineage.

Surgical adhesives in ophthalmology: history and current trends.

Tissue adhesives are gaining popularity in ophthalmology, as they could potentially reduce the complications associated with current surgical methods. An ideal tissue adhesive should have superior tensile strength, be non-toxic and anti-inflammatory, improve efficiency and be cost-effective. Both synthetic and biological glues are available. The primary synthetic glues include cyanoacrylate and the recently introduced polyethylene glycol (PEG) derivatives, while most biological glues are composed of fibrin. Cyanoacrylate has a high tensile strength, but rapidly polymerises upon contact with any fluid and has been associated with histotoxicity. Fibrin induces less toxic and inflammatory reactions, and its polymerisation time can be controlled. Tensile strength studies have shown that fibrin is not as strong as cyanoacrylate. While more research is needed, PEG variants currently appear to have the most promise. These glues are non-toxic, strong and time-effective. Through MEDLINE and internet searches, this paper presents a systematic review of the current applications of surgical adhesives to corneal, glaucoma, retinal, cataract and strabismus surgeries. Our review suggests that surgical adhesives have promise to reduce problems in current ophthalmic surgical procedures.