Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance

Tumor microenvironment induces innate RAF-inhibitor resistance through HGF secretion

Drug resistance remains a vexing problem in the treatment of cancer patients. While many studies have focused on cell autonomous mechanisms of drug resistance, we hypothesized that the tumor microenvironment may confer innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anti-cancer drugs. We found that stroma-mediated resistance is surprisingly common – particularly to targeted agents. We further characterized the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibition because most of these patients exhibit some degree of innate resistance1-4. Proteomic analysis showed that stromal secretion of the growth factor hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the MAPK and PI3K/AKT pathways, and immediate resistance to RAF inhibition. Immunohistochemistry confirmed stromal HGF expression in patients with BRAF-mutant melanoma and a statistically significant correlation between stromal HGF expression and innate resistance to treatment. Dual inhibition of RAF and MET resulted in reversal of drug resistance, suggesting RAF/MET combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, these studies indicate that the systematic dissection of tumor-microenvironment interactions may reveal important mechanisms underlying drug resistance

Low‐Value Proton Pump Inhibitor Prescriptions Among Older Adults at a Large Academic Health System

BACKGROUND:Older adults are particularly vulnerable to complications from proton pump inhibitor (PPI) drugs. We sought to characterize the prevalence of potentially low-value PPI prescriptions among older adults to inform a quality improvement (QI) intervention. METHODS:We created a cohort of patients, aged 65 years or older, receiving primary care at a large academic health system in 2018. We identified patients currently prescribed any PPI using the electronic health record (EHR) medication list (current defined as September 1, 2018). A geriatrician, a gastroenterologist, a QI expert, and two primary care physicians (PCPs) created multidisciplinary PPI appropriateness criteria based on evidenced-based guidelines. Supervised by a gastroenterologist and PCP, two internal medicine residents conducted manual chart reviews in a random sample of 399 patients prescribed PPIs. We considered prescriptions potentially low value if they lacked a guideline-based (1) short-term indication (gastroesophageal reflux disease [GERD]/peptic ulcer disease/Helicobacter pylori gastritis/dyspepsia) or (2) long-term (>8 weeks) indication (severe/refractory GERD/erosive esophagitis/Barrett esophagus/esophageal adenocarcinoma/esophageal stricture/high gastrointestinal bleeding risk/Zollinger-Ellison syndrome). We used the Wilson score method to calculate 95% confidence intervals (CIs) on low-value PPI prescription prevalence. RESULTS:Among 69 352 older adults, 8729 (12.6%) were prescribed a PPI. In the sample of 399 patients prescribed PPIs, 63.9% were female; their mean age was 76.2 years, and they were seen by 169 PCPs. Of the 399 prescriptions, 143 (35.8%; 95% CI = 31.3%-40.7%) were potentially low value-of which 82% began appropriately (eg, GERD) but then continued long term without a guideline-based indication. Among 169 PCPs, 32 (18.9%) contributed to 59.2% of potentially low-value prescriptions. CONCLUSION:One in eight older adults were prescribed a PPI, and over one-third of prescriptions were potentially low-value. Most often, appropriate short-term prescriptions became potentially low value because they lacked long-term indications. With most potentially low-value prescribing concentrated among a small subset of PCPs, interventions targeting them and/or applying EHR-based automatic stopping rules may protect older adults from harm. J Am Geriatr Soc 67:2600-2604, 2019

Low‐Value Proton Pump Inhibitor Prescriptions Among Older Adults at a Large Academic Health System

BackgroundOlder adults are particularly vulnerable to complications from proton pump inhibitor (PPI) drugs. We sought to characterize the prevalence of potentially low-value PPI prescriptions among older adults to inform a quality improvement (QI) intervention.MethodsWe created a cohort of patients, aged 65 years or older, receiving primary care at a large academic health system in 2018. We identified patients currently prescribed any PPI using the electronic health record (EHR) medication list (current defined as September 1, 2018). A geriatrician, a gastroenterologist, a QI expert, and two primary care physicians (PCPs) created multidisciplinary PPI appropriateness criteria based on evidenced-based guidelines. Supervised by a gastroenterologist and PCP, two internal medicine residents conducted manual chart reviews in a random sample of 399 patients prescribed PPIs. We considered prescriptions potentially low value if they lacked a guideline-based (1) short-term indication (gastroesophageal reflux disease [GERD]/peptic ulcer disease/Helicobacter pylori gastritis/dyspepsia) or (2) long-term (>8 weeks) indication (severe/refractory GERD/erosive esophagitis/Barrett esophagus/esophageal adenocarcinoma/esophageal stricture/high gastrointestinal bleeding risk/Zollinger-Ellison syndrome). We used the Wilson score method to calculate 95% confidence intervals (CIs) on low-value PPI prescription prevalence.ResultsAmong 69 352 older adults, 8729 (12.6%) were prescribed a PPI. In the sample of 399 patients prescribed PPIs, 63.9% were female; their mean age was 76.2 years, and they were seen by 169 PCPs. Of the 399 prescriptions, 143 (35.8%; 95% CI = 31.3%-40.7%) were potentially low value-of which 82% began appropriately (eg, GERD) but then continued long term without a guideline-based indication. Among 169 PCPs, 32 (18.9%) contributed to 59.2% of potentially low-value prescriptions.ConclusionOne in eight older adults were prescribed a PPI, and over one-third of prescriptions were potentially low-value. Most often, appropriate short-term prescriptions became potentially low value because they lacked long-term indications. With most potentially low-value prescribing concentrated among a small subset of PCPs, interventions targeting them and/or applying EHR-based automatic stopping rules may protect older adults from harm. J Am Geriatr Soc 67:2600-2604, 2019

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance