Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers.

Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRASG12C inhibition.

The evolving treatment landscape of advanced urothelial carcinoma.

PURPOSE OF REVIEW: Bladder cancer is the 10th most common cancer in the world and the 6th most common cancer among men. In the past few years, several new agents have been approved for the treatment of urothelial tumors. In this paper, we review the evolving treatment landscape of advanced urothelial carcinoma (UC). RECENT FINDINGS: Since 2016, the Food and Drug Administration (FDA) has approved five immunotherapies targeting programmed cell death 1/programmed cell death 1 legend, an antinectin-4 antibody drug conjugate (ADC), and a fibroblast growth factor receptor (FGFR) inhibitor for the treatment of patients with advanced UC. Moreover, there are multiple targeted agents, immune checkpoint inhibitors (ICI), ADCs, and their combinations currently being tested in clinical studies with the goal of obtaining FDA approval. SUMMARY: Precision oncology efforts continue to advance our understanding of the UC biology and transform the existing treatment paradigms. An enlarging arsenal of treatment options promises further personalization of UC therapy.

Molecular Profiling of Metastatic Bladder Cancer Early-Phase Clinical Trial Participants Predicts Patient Outcomes.

Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The median progression-free survival was 4.2 months, the median overall survival was 9.6 months, and the overall response rate was 17.5%. TP53, ERBB2, PI3KCA, FGFR3, and ARID1A alterations were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively. Alterations in FGFR3 were almost mutually exclusive of TP53. More than half (64%) of patients with an FGFR alt received an FGFR inhibitor, 67% of which achieved disease control. Among patients with urothelial carcinoma histology, those harboring a TP53 alteration had a shorter median progression-free survival (PFS) compared with those whose tumors carry wild-type TP53. The reverse relationship was observed in patients harboring an FGFR alteration. IMPLICATIONS: Patients with platinum-refractory mBC derive clinical benefit from participating in early-phase clinical trials and their survival outcomes correlate with the genetic profile of the tumor. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/395/F1.large.jpg.

Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies.

PURPOSE: The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+). METHODS: A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation. RESULTS: Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16-0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04-0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25-1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation. CONCLUSION: Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

Next-generation characterization of the Cancer Cell Line Encyclopedia.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.