Drug-Resistant Mutations in ERK
The use of targeted therapeutics directed against BRAFV600-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAFV600-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor–resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents. Cancer Res; 74(23); 7079–89. ©2014 AACR.
We report the estimation of the percentage of stroma (POS) using digital pathology in a large population-ascertained cohort of primary melanomas. Consent was obtained from participants in the Leeds Melanoma Cohort Study to access and sample tumor FFPE blocks. H&E-stained slides were digitally scanned and blocks were sampled for gene expression studies using a tissue microarray needle; this yielded a core of tissue from which RNA was extracted and assayed using Illumina WGDASL.
Importance: Melanoma is a highly aggressive cancer with extremely poor late stage survival. Those with a previous melanoma diagnosis have a 9-fold increased risk for developing a second primary melanoma compared with the general population. Yet, guidelines for dermatologic follow-up full body skin examinations (FBSEs) after diagnosis of stage I melanoma are ill-defined and vary widely.
Introduction: The incidence of both melanoma and nonmelanoma skin cancer is increasing at an alarming rate, particularly for minority populations. Outcomes are often worse in these populations due to delayed detection and treatment, attributed to barriers such as decreased understanding about skin cancers and limited access to dermatological care from lack of insurance. Uninsured patients make up a smaller fraction of dermatology practices than would be predicted by their prevalence in the population.
Background: The incidence of melanoma and nonmelanoma skin cancer has been increasing in all age groups including children and adolescents. Prior studies in the pediatric population have shown low rates of sun protection behaviors and only modest improvement over the past several decades.
This study aimed to compare the quality of life (QoL) of patients with BCC against that of patients with relapse-free MM.
Background: Immune checkpoint inhibitors (ICI) such as anti-programmed death protein 1 (anti-PD-1) antibodies produce durable responses in a subset of cancer patients. ICI can produce immune-related adverse events (irAEs). Among the earliest and most common irAEs are skin toxicities. Several studies have associated the development of irAEs with increased treatment efficacy, though it remains unclear whether steroid treatment for irAEs interferes with the antitumor effects of ICI. We sought to evaluate the effect of cutaneous irAEs on treatment outcomes.
Background: Complementary and alternative medicine (CAM) is widely used by cancer patients, but data is scarce for skin cancer. It has been reported that ∼20% of NMSC patients and 40-50% of melanoma patients have used CAM.
Nivolumab, a checkpoint inhibitor of programmed cell death receptor-1 (PD-1), is used in the treatment of metastatic melanoma and nonsmall cell lung cancer. Blockade of PD-1 receptor releases inhibition of T-cell activation and allows for an antitumor immune response. As with many immune-mediated therapeutics, the most common cutaneous immune-related adverse events reported in association with nivolumab are vitiligo, rash and pruritis. Other autoimmune and inflammatory skin conditions such as psoriasiform or lichenoid eruptions, autoimmune blistering disorders, and sarcoidosis have also been reported.
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer after basal cell carcinoma. While most cases are cured by excision, a substantial number of patients will develop local, regional, or distant recurrences, with the number of cSCC-related deaths approaching that from melanoma. Several clinical decisions, including the extent of surgical margins, the use of adjuvant radiation or chemotherapy, and sentinel lymph node biopsy/completion dissection, could be informed by a patient ’s relative risk of recurrence.
The objective of this study was to determine if nonprimary site surgery is significantly associated with improved survival outcomes.