pyrimidinones and osimertinib

Osimertinib, an orally administered third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is widely approved for the first-line and second-line treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations. However, the rapid development of osimertinib resistance renders the unsustainable treatment benefit. Patients with EGFR -mutated NSCLC who develop osimertinib resistance, especially those acquiring relatively rare and 'off-target' resistance mutations, still lack effective therapeutic options for postosimertinib therapy. Herein, we reported a 73-year-old woman diagnosed with T1N3M1 lung adenocarcinoma harboring EGFR L858R mutation, who acquired two GNAS mutations (R201C and R201H) and lost the EGFR L858R mutation after progression on icotinib and osimertinib. The patient was subsequently treated with trametinib and there was no obvious tumor increase. Our study revealed that GNAS R201 can confer the osimertinib resistance in EGFR -positive NSCLC, and present the first report of the prevalence of GNAS R201C and R201H mutants in NSCLC which response to trametinib treatment. Our case suggests that trametinib could be a treatment option in NSCLC patients harboring GNAS -activating mutations.

Topics: Acrylamides; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Chromogranins; ErbB Receptors; Female; GTP-Binding Protein alpha Subunits, Gs; Humans; Indoles; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Pyrimidinones

Heterogeneity in the acquired genetic cause of osimertinib resistance leads to difficulties in understanding and addressing molecular mechanisms of resistance in clinical practice. Recent studies and clinical cases established that altered BRAF could drive osimertinib resistance in an EGFR-independent manner. Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. Disease control was maintained for 6 months. BRAF p.D594N is a kinase impaired mutation but leads to increased MEK/ERK signaling, which could activate the downstream signaling of EGFR and induce drug resistance. There has been preclinical evidence supporting dual inhibition of MEK and EGFR for overcoming this resistance. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.

Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; ErbB Receptors; Fibrosarcoma; Humans; Indoles; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones

Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Codon; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Mice; Mice, SCID; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Transfection; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Acrylamides; Aniline Compounds; ErbB Receptors; Humans; Imidazoles; Liquid Biopsy; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Osimertinib (AZD9291), a third-generation, mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), is an approved drug for patients who have non-small cell lung cancer (NSCLC) with activating EGFR mutations or those harboring a resistant T790M mutation. Unfortunately, all patients eventually relapse and develop resistance to osimertinib. The current study addressed whether ERK inhibition exerts effects similar to those produced by MEK inhibition in overcoming acquired resistance to osimertinib.. Drug effects on cell and tumor growth were assessed by measuring cell number alterations and colony formation in vitro and with xenografts in nude mice in vivo. Apoptosis was assessed with annexin V/flow cytometry and protein cleavage. Protein alterations in cells were detected with Western blot analysis. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively.. The combination of osimertinib with an ERK inhibitor synergistically decreased the survival of osimertinib-resistant cell lines with enhanced induction of apoptosis and effectively inhibited the growth of osimertinib-resistant xenografts in nude mice. Moreover, the combination of an MEK or ERK inhibitor with a first-generation (eg, erlotinib) or second-generation (eg, afatinib) EGFR-TKI also very effectively inhibited the growth of osimertinib-resistant cells in vitro and of tumors in vivo, although these cell lines were cross-resistant to first-generation or second-generation EGFR-TKIs.. The current findings emphasize the importance of targeting MEK/ERK signaling in maintaining the long-term benefit of osimertinib through overcoming acquired resistance to osimertinib, warranting further investigation of this therapeutic strategy to improve the therapeutic efficacy of osimertinib in the clinic.

Topics: Acrylamides; Afatinib; Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Therapy, Combination; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mice; Mice, Nude; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Neoplastic Stem Cells; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations.. Two patients with anEGFR exon 19 deletion and a T790 M mutation, both treated with osimertinib, acquired a BRAF V600E mutation at disease progression. Following the recommendation of the molecular tumor board, a concurrent combination of dabrafenib and trametinib plus osimertinib was administered.. Because of toxicity, one patient ultimately received a reduced dose of dabrafenib and trametinib combined with a normal dose of osimertinib. Clinical response in this patient lasted for 13.4 months. Re-biopsy upon tumor progression revealed loss ofBRAF V600E and emergence of EGFR C797S. The other patient, treated with full doses of the combined therapy, had progression with metastases in lung and brain one month after starting therapy.. BRAF V600E may be a resistance mechanism induced by osimertinib in EGFR-mutated advanced NSCLC. Combined treatment using dabrafenib/trametinib concurrently with osimertinib needs to be explored for osimertinib-induced BRAF V600E mutation.

Topics: Acrylamides; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Acrylamides; Adenocarcinoma of Lung; Angiopoietin-Like Protein 6; Angiopoietin-like Proteins; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Neoplasm Metastasis; Oncogene Proteins, Fusion; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones