RESUMEN
The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Genómica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Osteonecrosis is a multifactorial process that can affect different skeletal structures of the body. Osteonecrosis of the jaw associated with bevacizumab, steroids and bisphosphonates, alone or in combination, is a well-documented phenomenon. There are few cases of involvement of the appendicular skeleton. Magnetic resonance imaging is the most sensitive method for diagnosis. We hereby report two cases of osteonecrosis in the right tibia and in bilateral femoral heads in patients with adenocarcinoma of the lung and ovarian papillary serous carcinoma, respectively, that developed the complication after long-term bevacizumab exposure. Long-term exposure to antiangiogenic treatment may be a potential risk factor. Oncologists should be aware that osteonecrosis is a rare but real toxicity associated with bevacizumab and other antiangiogenics, which can occur in locations different from the jaw.
