ABSTRACT
Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These 'persister' cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.
Subject(s)
Acrylamides , Drug Resistance, Neoplasm , ErbB Receptors , Indoles , Lung Neoplasms , Mutation , Pyrimidines , Transcription Factors , Humans , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , ErbB Receptors/genetics , ErbB Receptors/metabolism , Drug Resistance, Neoplasm/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Cell Line, Tumor , Acrylamides/pharmacology , Acrylamides/therapeutic use , YAP-Signaling Proteins/metabolism , YAP-Signaling Proteins/genetics , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Gefitinib/pharmacology , Hippo Signaling Pathway , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Signal Transduction , TEA Domain Transcription Factors , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Clustered Regularly Interspaced Short Palindromic Repeats , CRISPR-Cas SystemsABSTRACT
OBJECTIVE: Pain remains a common complication after gynecologic laparoscopy. Use of local anesthesia may be beneficial in reducing postoperative pain. We performed a systematic review and meta-analysis to assess whether local anesthetic decreases postoperative pain after laparoscopic gynecologic procedures. DATA SOURCES: We searched Cumulative Index to Nursing and Allied Health Literature, Embase, and Medline from inception to November 2020 using Medical Subject Headings and free text combinations. METHODS OF TRIAL SELECTION: We included randomized controlled trials of patients undergoing gynecologic laparoscopy receiving port site subcutaneous, subfascial, or intraperitoneal local anesthetic compared with placebo or no intervention. We included 20 trials (1861 participants) with size varying between 28 and 164 participants. TABULATIONS, INTEGRATION, AND RESULTS: Meta-analysis was performed with RevMan 5.3 (Cochrane Collaboration, London, United Kingdom), with standard mean differences (SMDs) and random-effects model. Port site infiltration reduces postoperative pain at 4 hours (SMD -0.25; 95% confidence interval [CI], -0.44 to -0.06; 4 trials; 545 participants) and 6 hours (SMD -0.44; 95% CI, -0.82 to -0.06; 4 trials; 455 participants) after surgery. The administration of intraperitoneal local anesthetics reduces pain at 6 hours (-1.42; 95% CI, -3.22 to -0.30; 4 trials; 277 participants) after surgery. CONCLUSIONS: The use of port site and intraperitoneal local anesthetic decreases immediate postoperative pain in patients undergoing gynecologic laparoscopy, although its impact on analgesia requirements is unclear. Routine usage of local anesthetics should be considered for people undergoing gynecologic laparoscopy.