Magic™ Anti-RB (Phospho Thr821) monoclonal antibody, clone 35B8

The aim of this study was to characterize secondary kinase mutations in Chinese patients with imatinib-resistant gastrointestinal stromal tumors (GISTs). Mutations in receptor tyrosine kinase (KIT; exons 9, 11, 13, 14, 17, and 18) and platelet-derived growth factor-alpha (PDGFRA; exons 12, 14, and 18) were analyzed by direct sequencing. After imatinib treatment, 425 cancer-related target genes were analyzed by next generation sequencing (NGS) in imatinib-resistant patients. Correlation of sequencing results with clinicopathologic features were analyzed. We identified 320 patients with secondary acquired resistance. We determined that 65.63% (210/320) of resistant patients had secondary KIT mutations in exon 13 (n = 134), exon 14 (n = 10), or exon 17 (n = 66), and 4.38% (14/320) had additional PDGFRA mutations in exon 14 (n = 3) or exon 18 (n = 11). All secondary KIT mutations were missense mutations and were mostly located in kinase domains. Ninety-six imatinib-resistant GIST patients did not have secondary KIT or PDGFRA mutations. Common independent mutation events were found in retinoblastoma protein 1 (RB1) (18/96 cases), SWI/SNF-related matrix associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) (16/96 cases), and myc-associated factor X (MAX) (10/96 cases). RB1 or SMARCB1 mutations coexisted with activation of other oncogenes in 6 or 15 cases, respectively. Multiple mutations were also seen in cases with MAX mutations. These mutations are frequently associated with clinicopathological factors. Secondary mutations of KIT/PDGFRA were the most important contributors in GISTs developing resistance to imatinib treatment. Additional genetic events including RB1, SMARCB1, and MAX except secondary KIT/PDGFRA mutations are the most common for GISTs to evolve into resistant disease. Clinical assessment of the effect of these mutations may benefit existing risk assessment models and selection of adjuvant therapies in GIST patients.

Until recently, the treatment of bladder cancer, for several years, was limited to surgery and to immunotherapy or chemotherapy. Currently, the extensive analysis of molecular alterations has led to novel treatment approaches. The advent of polymerase chain reaction and genomic hybridization techniques has allowed to investigate alterations involved in bladder cancer at DNA level. By this way, bladder cancers can be classified as papillary or non-papillary based on genetic alterations with activation or mutations in FGFR3 papillary tumors and with inactivation or mutations involving TP53 and RB1 in non-papillary tumors. Recently, the patterns of gene expression allow to differentiate basal and luminal subtypes as reported in breast cancer. In particular, basal cancers are composed of squamous and sarcomatoid pathological findings, while luminal cancers are composed of papillary finding features and genetic mutations (FGFR3). In particular, specific investigative studies demonstrated that luminal cancers are associated with secondary muscle invasive cancer while basal tumors are related to advanced disease since they are often metastatic at diagnosis. Moreover, from therapeutic point of view, different researchers showed that mutations of DNA are related to the sensitivity of bladder cancer while performing cisplatin chemotherapy. In this prospective, the bladder cancer molecular subtyping classification might allow identifying the set of patients who can safely avoid neoadjuvant chemotherapy likely because of the low response to systemic chemotherapy (chemoresistant tumors). In this context, the Cancer Genome Atlas (TCGA) project has improved the knowledge of the molecular targets of invasive urothelial cancers allowing the researchers to propose hypothesis suggesting that agents targeting the genomic alterations may be an effective strategy in managing these cancers, which occur in about 68% of muscle invasive cancers. A future goal will be to combine treatment strategies of invasive bladder cancers according to their genetic mutational load defined by molecular pathology.