👤 Edmundo Arteaga

Adverse drug responses (ADRs) result in over 7,000 deaths annually. Pharmacogenomic studies have shown that many ADRs are partially attributable to genetics. However, emerging data suggest that epigenetic mechanisms, such as DNA methylation (DNAm) also contribute to this variance. Understanding the impact of DNA methylation on drug response may minimize ADRs and improve the personalization of drug regimens. In this work, we identify DNA methylation sites that likely impact drug response phenotypes for anticoagulant and cardiometabolic drugs. We use instrumental variable analysis to integrate genome-wide association study (GWAS) summary statistics derived from electronic health records (EHRs) within the U.K. Biobank (UKBB) with methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC). This approach allows us to achieve a robust sample size using the largest publicly available pharmacogenomic GWAS. For warfarin, we find 71 DNAm sites. Of those, 8 are near the gene VKORC1 and 48 are on chromosome 6 near the human leukocyte antigen (HLA) gene family. We also find 2 warfarin DNAm sites near the genes CYP2C9 and CYP2C19. For statins, we identify 17 DNAm sites. Eight are near the APOB gene, which encodes a carrier protein for low-density lipoprotein cholesterol (LDL-C). We find no novel significant epigenetic results for metformin. Show less

We report herein a phase Ib trial to determine the safety, tolerability, and antitumor activity of erdafitinib, a pan-FGFR tyrosine kinase inhibitor, with fulvestrant and palbociclib in patients with hormone receptor-positive/HER2-negative metastatic breast cancers (NCT03238196). Thirteen patients were enrolled on the escalation phase in a traditional 3 + 3 trial design to determine the maximum tolerated dose (MTD). Subsequently, 22 patients were treated at the established MTD during the expansion phase. All patients had received prior treatment with cyclin-dependent kinase-4/6 inhibitors and endocrine therapy, and 29 showed FGFR pathway alterations in their tumors. The MTD of erdafitinib was 6 mg taken orally once daily when combined with palbociclib and fulvestrant. The triple combination showed clinically manageable tolerability. Most common adverse events were neutropenia, likely attributable to palbociclib, and oral mucositis and hyperphosphatemia, attributable to erdafitinib. Three patients showed a partial response, one of them lasting more than 2.5 years, despite lacking detectable FGFR1 to FGFR4 somatic alterations. FGFR1 amplification was not associated with response to FGFR inhibition, but high FGFR1 protein expression, measured by IHC, correlated with longer progression-free survival within the FGFR1-amplified cohort. There was no correlation between FGFR1 copy number and FGFR1 protein levels in specimens from metastatic sites, potentially highlighting the need for a more recent metastatic tumor biopsy for biomarker evaluation. The trial endpoint was met establishing the MTD of erdafitinib at 6 mg. Whereas the triplet regimen may pose tolerability challenges, alterative doublets with selective FGFR1 inhibitors in patients with FGFR1-dependent tumors, possibly administered in sequence, are worthy of further investigation. Show less

FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1 Show less

Anti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYND8 specifically confers resistance to cancer cells against trastuzumab and/or pertuzumab. Mechanistically, ZMYND8 enhances cPLA2α expression in resistant tumor cells through inducing c-Myc. cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit phosphatidylcholine breakdown into diacylglycerol, which diminishes protein kinase C activity leading to interleukin-27 secretion. Supplementation with interleukin-27 protein counteracts cPLA2α loss to reinforce trastuzumab resistance in HER2+ tumor cells and patient-derived organoids. Upregulation of ZMYND8, c-Myc, cPLA2α, and IL-27 is prevalent in HER2+ breast cancer patients following HER2-targeted therapies. Targeting c-Myc or cPLA2α effectively overcomes anti-HER2 therapy resistance in patient-derived xenografts. Collectively, this study uncovers a druggable signaling cascade that drives resistance to HER2-targeted therapies in HER2+ breast cancer. Show less

Despite fibroblast growth factor receptor ( EAY131-K1 was an open-label, single-arm, phase II study with central confirmation of presence of Thirty-five patients were enrolled into this study with 18 included in the prespecified primary efficacy analysis. The median age of the 18 patients was 60 years, and 78% had received ≥3 previous lines of therapy. There were no confirmed responses to erdafitinib; however, five patients experienced stable disease (SD) as best response. One patient with an Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring Show less

Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions. Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner. Show less

Hypertrophic cardiomyopathy (HC) is the most frequent cardiac hereditary disease, caused by mutations in sarcomere protein coding genes. Although more than 430 mutations have been identified in several continents and countries, there have been no reports of mutations in Brazil. To carry out a genetic study to identify genetic mutations that cause HC in a group of patients in Espirito Santo, Brazil. Using the SSCP technique, 12 exons from the three main genes involved in HC were studied: exons 15, 20, 21, 22 and 23 of the beta-myosin heavy chain gene (MYH7), exons 7, 16, 18, 22 and 24 of the myosin binding protein C gene (MYBPC3) and exons 8 and 9 of troponin T gene (TNNT2). 16 alterations were found, including two mutations, one of them possibly pathogenic in the MYBPC3 gene (p. Glu441Lys) and another pathogenic one, previously described in the TNNT2 gene (p.Arg92Trp), 8 rare sequence variations and 6 sequence variations with allelic frequency higher than 1% (polymorphisms). These data allow the conclusion that the genotyping of patients is feasible in our country. It is possible that the isolated p.Glu441Lys variant identified in exon 16 of the MYBPC3 gene is pathogenic, promoting a milder phenotype than that found when in association with other mutations. The p.Arg92Trp variant in the exon 9 of TNNT2 gene does not promote such a homogeneous phenotype as previously described and it can lead to severe hypertrophy. Show less