DDX3X Mutations Driving Natural Killer/T-cell Lymphoma
Natural killer/T-cell lymphoma (NKTCL), a form of non-Hodgkin's lymphoma, occurs predominantly in Asians, Mexicans, and South Americas. Jiang and colleagues sequenced exomes from 25 patients, validating mutations in 80 additional individuals with NKTCL. Surprisingly, 20% of patients with NKTCL harbored mutations in the ATP-dependent RNA helicase gene, DDX3X, which was almost mutually exclusive with mutations in TP53, STAT3/5, and genes encoding epigenetic modification enzymes. Mutation of DDX3X correlated with a more aggressive clinical course relative to NKTCL with wild-type DDX3X. NKTCL-associated DDX3X mutations impaired DDX3X helicase activity and increased in NF-κB and MAPK pathway signaling. Thus, DDX3X appears to be a major driver of oncogenesis in NKTCL.
Infiltrating Immune Cells and Cancer
Gentles and colleagues, through a herculean effort, assembled, curated, and integrated public cancer global gene expression profiles (GEP) with annotated clinical outcomes for ∼18,000 patients, covering 39 different cancers into a unified on-line resource dubbed Prediction of Clinical Outcomes from Genomic (PRECOG) profiles. The authors applied a computational method for deconvoluting the relative composition of immune cell types using GEPs from the bulk tumor to the PRECOG database. They discovered prognostic correlations between: (i) higher levels of intratumoral T-cell subsets, specifically γδ T cells, with better overall survival; and (ii) increasing levels of intratumoral myeloid subsets, primarily polymorphonuclear leukocytes, with poorer overall survival. PRECOG enables a robust retrospective view of the potential prognostic landscape of genes and intratumoral immune cells across human cancers, as well as a hypothesis-generating tool for future studies.
ERK Dimerization Inhibitors
Resistance to inhibitors of BRAF and MEK typically occurs through reactivation of ERK signaling. Herrero and colleagues developed a small molecule, DEL-22379, that inhibits ERK dimerization, required to maintain ERK signaling in the extranuclear compartment. This novel strategy decreased proliferation of cancer cells harboring mutated BRAF (V600E) or RAS (Q61L or G12V) and correlated to ERK dimer-monomer ratio, and extranuclear/nuclear ERK localization. Zebrafish harbor ERK orthologs that lack the requirement to dimerize. In a transgenic RAS-V12 zebrafish model, MEK inhibitors, but not DEL-22379, inhibited melanoma formation, supporting that efficacy of DEL-22379 is tied to its inhibition of ERK dimerization. DEL-22379 also inhibited proliferation of tumor cells with engineered resistance to BRAF and MEK inhibitors, suggesting that this strategy has the potential to overcome some challenges encountered with clinical BRAF, MEK, and ERK inhibitors to date.
Neuroblastoma: All but Silent
Taking advantage of paired analysis, two new studies examine trios of primary tumor DNA, recurrent tumor DNA, and constitutional DNA from neuroblastoma tumors. Examining 23 trios, Eleveld and colleagues (1) demonstrated a median increase of 14 nonsynonymous mutations at recurrence compared with primary tumor. Analysis of the cancer cell fraction with a given mutation suggested subclonal outgrowth from the primary tumor and clonal enrichment of mutations over time. Moreover, RAS-MAPK mutations that resulted in activation of the pathway were selected for in recurrent tumors after chemotherapy. Schramm and colleagues (2) also demonstrated an increase in mutations with recurrence. In addition, they demonstrated striking temporal and spatial intratumoral heterogeneity based on analysis of tumor samples from a single patient with multiple recurrences. Neuroblastoma is a dynamic tumor for which understanding disease mechanisms at recurrence is critical.
Molecular Analysis of Ductal Carcinoma In Situ
To provide insights into progression, Abba and colleagues performed full exome, transcriptome, and methylome analysis of high-grade DCIS (HG-DCIS) and normal breast epithelial samples. Mutations affecting potential drivers were observed in 62% of cases, including mutations in PIK3CA, TP53, GATA3, and MLL3. Single HG-DCIS cases showed mutations in CDH1, MAP2KA, TBX3, NF1, ATM, and ARID1A. Large chromosomal copy number alterations occurred in 83% of HG-DCIS lesions, suggesting that these might precede selection of cancer-driver mutations. The authors also identified two DCIS subgroups using integrated pathway-based modeling analysis of RNA-seq data. The more aggressive subgroup DCIS-C1 had properties resembling a tumor-associated immune suppressive phenotype. Interestingly, the authors found that all lesions showed TP53 pathway inactivation. Thus, although HG-DCIS represents a pre-invasive tumor, its molecular profile is indistinguishable from invasive breast cancer.
Undruggable Targets
The phthalimides are small molecules used to treat hematologic malignancies. One mechanism of action utilizes cereblon-cullin-RING ubiquitin ligase (CRL)-dependent proteasomal degradation of IKZF1 and IKZF3 transcription factor complexes. Co-opting this mechanism of action, Winter and colleagues developed phthalimide-directed ligand-induced target protein proteasomal degradation. Chemical synthesis of a small molecule phthalimide-ligand conjugate directed against the BRD4 transcriptional coactivator protein demonstrated highly specific and more potent antitumor activity than the parent nonconjugate inhibitory small molecule JQ1 in vitro and in vivo. Similar but less extensive validation was also performed against the FKBP12 (FKBP1A) protein target. This phthalimide-conjugating methodology opens the exciting possibility of repurposing binding ligands that lack intrinsic inhibitory activity to enable therapeutic targeting of “undruggable” oncogenic drivers in cereblon expressing cancers.
Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.
- ©2015 American Association for Cancer Research.
Volume 75, Issue 18
