Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing.

Introduction: Genomic alterations in the juxtamembrane exon 14 splice sites in NSCLC lead to increased MET stability and oncogenesis. We present the largest cohort study of MET Exon 14 (METex14) using whole transcriptome sequencing. Methods: A total of 21,582 NSCLC tumor samples underwent complete genomic profiling with next-generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, whole transcriptome sequencing). Clinicopathologic information including programmed death-ligand 1 and tumor mutational burden were collected and RNA expression for mutation subtypes and MET amplification were quantified. Immunogenic signatures and potential pathways of invasion were characterized using single-sample gene set enrichment analysis and mRNA gene signatures. Results: A total of 533tumors (2.47%) with METex14 were identified. The most common alterations were point mutations (49.5%) at donor splice sites. Most alterations translated to increased MET expression, with MET co-amplification resulting in synergistic increase in expression (q < 0.05). Common coalterations were amplifications of MDM2 (19.0% versus 1.8% wild-type [WT]), HMGA2 (13.2% versus 0.98% WT), and CDK4 (10.0% versus 1.5% WT) (q < 0.05). High programmed death-ligand 1 > 50% (52.5% versus 27.3% WT, q < 0.0001) and lower proportion of high tumor mutational burden (>10 mutations per megabase, 8.3% versus 36.7% WT, p < 0.0001) were associated with METex14, which were also enriched in both immunogenic signatures and immunosuppressive checkpoints. Pathways associated with METex14 included angiogenesis and apical junction pathways (q < 0.05). Conclusions: METex14 splicing alterations and MET co-amplification translated to higher and synergistic MET expression at the transcriptomic level. High frequencies of MDM2 and CDK4 co-amplifications and association with multiple immunosuppressive checkpoints and angiogenic pathways provide insight into potential actionable targets for combination strategies in METex14 NSCLC.

Mdm2-RNA Interactions as a Target for Cancer Therapy: It's Not All About p53.

In this issue of Cancer Cell, Gu et al. characterize small molecules that inhibit the interaction of Mdm2 with the mRNA that encodes the anti-apoptotic XIAP, simultaneously decreasing expression of both proteins. This represents a novel approach that has relevance in tumor cells independent of p53 status.

p53-independent effects of Mdm2.

Mdm2 is best known as the primary negative regulator of p53, but a growing body of evidence suggests that Mdm2 also has a number of functions independent of its role in regulating p53. Although these functions are not yet well-characterized, they have been implicated in regulating of a number of cellular processes, including cell-cycle control, apoptosis, differentiation, genome stability, and transcription, among others. It appears that Mdm2 exerts these functions through a surprisingly wide variety of mechanisms. For example, it has been shown that Mdm2 can ubiquitinate alternative targets, can stimulate the activity of transcription factors, and can directly bind to mRNA to regulate its stability. Dysregulation of p53-independent functions could be responsible for the oncogenic properties of Mdm2 seen even in the absence of p53, and may explain why approximately 10 % of human tumors overexpress Mdm2 instead of inactivating p53 through other mechanisms. As the p53-independent functions of Mdm2 present novel targets for potential therapeutic interventions, fully characterizing these cellular and pathogenic roles of Mdm2 will be important in the study of tumor biology and the treatment of cancer.