The pharmacogenomics of drug resistance to protein kinase inhibitors

Dysregulation of growth factor cell signaling is a major driver of most human cancers. This has led to development of numerous drugs targeting protein kinases, with demonstrated efficacy in the treatment of a wide spectrum of cancers. Despite their high initial response rates and survival benefits, the majority of patients eventually develop resistance to these targeted therapies. This review article discusses examples of established mechanisms of drug resistance to anticancer therapies, including drug target mutations or gene amplifications, emergence of alternate signaling pathways, and pharmacokinetic variation. This reveals a role for pharmacogenomic analysis to identify and monitor for resistance, with possible therapeutic strategies to combat chemoresistance

KELT-18b: Puffy Planet, Hot Host, Probably Perturbed

We report the discovery of KELT-18b, a transiting hot Jupiter in a 2.87-day orbit around the bright (V = 10.1), hot, F4V star BD+60 1538 (TYC 3865-1173-1). We present follow-up photometry, spectroscopy, and adaptive optics imaging that allow a detailed characterization of the system. Our preferred model fits yield a host stellar temperature of 6670 ± 120 K and a mass of 1.524^(+0.069)_(-0.068) M⊙, situating it as one of only a handful of known transiting planets with hosts that are as hot, massive, and bright. The planet has a mass of 1.18 ± 0.11 M_J, a radius of 1.570^(+0.042)_(-0.036) R_J, and a density of 0.377 ± 0.040 g cm^(-3), making it one of the most inflated planets known around a hot star. We argue that KELT-18b's high temperature and low surface gravity, which yield an estimated ~600 km atmospheric scale height, combined with its hot, bright host, make it an excellent candidate for observations aimed at atmospheric characterization. We also present evidence for a bound stellar companion at a projected separation of ~1100 au, and speculate that it may have contributed to the strong misalignment we suspect between KELT-18's spin axis and its planet's orbital axis. The inferior conjunction time is 2457542.524998 ± 0.000416 (BJD_(TDB)) and the orbital period is 2.8717510 ± 0.0000029 days. We encourage Rossiter–McLaughlin measurements in the near future to confirm the suspected spin–orbit misalignment of this system

Harry H. Lothrop Correspondence

Entries include a poem about Robert Frost and handwritten and typed letters from Lothrop

MAGED2: A novel p53-dissociator

The tumor suppressor protein p53 is a transcription factor that is frequently mutated in human cancers. In response to DNA damage, unmutated or wild-type (wt) p53 protein is stabilized and activated by post-transcriptional modifications that enable it to induce either apoptosis or cell cycle arrest. Using a yeast p53-dissociator assay, we identified MAGED2 as a potential negative regulator of wt p53 activity. Subsequently, using co-immunoprecipitation and reporter gene assays in human cultured cells that are often adopted for functional analysis of p53 we demonstrated that MAGED2 interacted physically with p53 and modified its activity. Finally, we were able to illustrate expression of both p53 and MAGED2 within the same subcellular compartment, i.e. either nucleus or cytoplasm, in 2,682 human cancer tissue specimens using a common cancer tissue microarray and antibodies against MAGED2 and p53. The present results implicate MAGED2, a novel protein, as a p53-dissociator

RNA expression of the molecular signature genes for metastasis in colorectal cancer

Colorectal cancer is an endemic disease in the Western world. Search for molecular signatures present in primary tumors that predict tumor metastasis potential has been proposed and in particular, a 17-gene molecular signature is associated with poor survival in breast cancer, prostate cancer, meduloblastoma and lymphoma in a recent study. Using quantitative real-time PCR assay (qPCR), our study observed tumor-normal differential RNA expression in 15 of these 17 genes in a cohort of 52 stage III colorectal cancer patients (all P0.05), two distinct groups among these genes were observed with Spearman correlation scores >0.6 (P0.05), but the recurrence group had more patients with mucinous tumors (9/12 vs. 7/25, P<0.05) and more lymph node involvement (median 7.2 vs. 2.5, P<0.05) compared to the non-recurrence group. Moreover, survival analysis revealed a significant difference in patient overall survival time between low and high tumor RNA levels for 1 of the 17 genes (PTTG1, P=0.024). Our qPCR validation study confirms the importance of most 17-gene molecular signature genes with differential RNA expression and suggests the relevance of PTTG1 for survival in colorectal cancers

Carbamazepine, HLA-B*1502 and risk of Stevens–Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations

Recently, the USA FDA has made a labeling change to the drug information contained in carbamazepine. Owing to recent data implicating the HLA allele B*1502 as a marker for carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in Han Chinese, the FDA recommends genotyping all Asians for the allele. This allele is seen in high frequency in many Asian populations other than Han Chinese, but there are few data on whether the allele is a marker for this severe outcome in anyone other than Han Chinese. In fact, the association has not been found in Caucasian patients. We review the data that prompted this recommendation, list data for other ethnic groups, both Asian and non-Asian, and briefly discuss the implication of this recommendation for clinical practice

Pharmacogenomics as a risk mitigation strategy for chemotherapeutic cardiotoxicity

Damage to the heart can result from both traditional chemotherapeutic agents, such as doxorubicin, and newer ‘targeted’ therapies, such as trastuzumab. This chemotherapeutic cardiotoxicity is potentially life-threatening and necessitates limiting or discontinuing an otherwise-effective cancer treatment. Clinical strategies focus on surveillance rather than prevention, although there are no specific therapies for this highly morbid adverse effect. Current models for prospectively predicting risk of chemotherapeutic cardiotoxicity are limited. Cardiotoxicity can occur idiosyncratically in patients without obvious demographic risk factors, suggesting a genetically determined susceptibility, and candidate-gene studies have identified a limited number of variants that increase risk. In this commentary we indicate a need for more powerful means to identify risk prospectively, and suggest that broad pharmacogenomic approaches may be fruitful

Using germline genotype in cancer pharmacogenetic studies

Pharmacogenetics provides great opportunity for improving both the chance of therapeutic benefit and the ability to avoid adverse drug events. To date, the majority of pharmacogenetic studies have been performed using germline DNA. DNA collection in most clinical trials provides a wealth of samples from which pharmacogenetic studies can be launched. However, there is concern that the data from germline DNA pharmacogenetics might be of limited value for diseases, such as cancer, where germline variants may not adequately represent the genetic data obtained from the somatic DNA. In this perspective, we evaluate the literature that compares pharmacogenetic variants between germline DNA and matched somatic DNA. The analysis of these studies indicates that there is almost complete concordance between germline and somatic DNA in variants of pharmacogenetic genes. Although somatic variants are clinically significant and independently provide genetic information that cannot be gained from the germline, the use of germline DNA for pharmacogenetic studies is achievable and valuable. This use of germline DNA offers great opportunities for the implementation of individualized therapy

A Comparison of Association Methods for Cytotoxicity Mapping in Pharmacogenomics

Cytotoxicity assays of immortalized lymphoblastoid cell lines (LCLs) represent a promising new in vitro approach in pharmacogenomics research. However, previous studies employing LCLs in gene mapping have used simple association methods, which may not adequately capture the true differences in non-linear response profiles between genotypes. Two common approaches summarize each dose-response curve with either the IC50 or the slope parameter estimates from a hill slope fit and treat these estimates as the response in a linear model. The current study investigates these two methods, as well as four novel methods, and compares their power to detect differences between the response profiles of genotypes under a variety of different alternatives. The four novel methods include two methods that summarize each dose-response by its area under the curve, one method based off of an analysis of variance (ANOVA) design, and one method that compares hill slope fits for all individuals of each genotype. The power of each method was found to depend not only on the choice of alternative, but also on the choice for the set of dosages used in cytotoxicity measurements. The ANOVA-based method was found to be the most robust across alternatives and dosage sets for power in detecting differences between genotypes