Therapies that activate the tumor suppressor p53 have significant potential therapeutic utility. Using a phenotypic screen for wild-type p53 transcription, Ladds and colleagues identified over 100 small molecules that activated p53 in cells. A series of tetrahydroindazoles (HZ00) inhibitors of dihydroorotate dehydrogenase (DHODH) blocked de novo pyrimidine nucleotide synthesis. Through crystallization of DHODH with a more potent analog, HZ05, they demonstrated that (R)-HZ05 was the active enantiomer. DHODH was a frequent target for structurally diverse compounds, as they also identified twelve other DHODH inhibitor chemotypes. Treatment with HZ compounds resulted in cells accumulating in S-phase, increasing p53 synthesis, and synergizing with inhibitors of p53 degradation to reduce tumor growth in vivo. The authors propose a novel strategy to promote cancer killing by p53, instead of its reversible effect on cell-cycle arrest.
Expert Commentary: This work uncovers the therapeutic implications of DHODH inhibition in potentiating blockade of p53 degradation.
Casein Kinase 1α Promotes Autophagy in Lung Cancer
CK1α acts as a tumor suppressor in some cancers, often in cooperation with p53. Cai and colleagues show that CK1α induced autophagic flux in non-small cell lung cancer (NSCLC) cells. Silencing of CK1α attenuated expression of autophagy genes. Reciprocally, induction of autophagy increased expression of CK1α, whereas inhibition of autophagy decreased levels of CK1α. CK1α regulates autophagy by associating with the carboxyl-terminal domain of PTEN, which displaces the ubiquitin ligase NEDD4-1, increasing the stability of PTEN. Stabilized PTEN in turn attenuates AKT activity, increasing FOXO3a-induced transcription of the autophagy regulator ATG7. Blocking this CK1α-driven accumulation of ATG7 cooperated with oncogenic HRAS to promote tumorigenesis in lung epithelial cells. Thus, CK1α promotes autophagy and suppresses NSCLC growth in a PTEN-dependent manner, as loss of PTEN attenuates this activity.
Expert Commentary: CK1α functions as a tumor suppressor in NSCLC, where it functions as a potent regulator of autophagy.
Tumor Suppressor LncRNAs in Neuroblastoma
The lncRNA CASC15 and its antisense counterpart NBAT1 at the ch 6p22.3 locus house neuroblastoma risk-associated single-nucleotide polymorphisms. Mondal and colleagues show that reduced expression of these lncRNAs is associated with a poor outcome in patients and that knockdown inhibits differentiation. CASC15 overexpression promotes neuronal differentiation by destabilizing CHD7, a transcriptional activator of SOX9, via ubiquitin-mediated degradation. CASC15-003/NBAT1 act in trans and compensate for each other, recruiting USP36 from the nucleolus, destabilizing CHD7, and downregulating SOX9 expression.
Expert Commentary: This study identifies two sense/antisense lncRNAs at the neuroblastoma risk-associated 6p22.3 locus to be tumor suppressors. Although they act in trans with no overlapping sequence, these lncRNAs promote retinoic acid–induced differentiation of neuroblastoma cells through ubiquitin-mediated degradation of transcriptional regulators of dedifferentiation genes. These studies help elucidate the functional significance of neuroblastoma risk-associated loci and identify mechanisms of therapy resistance.
The TRAIL to Success Leads to NK Cells
Efforts to develop an activator of the TRAIL pathway to inhibit tumor growth have spanned two decades. Wagner and colleagues rediscovered a previously known but underexplored antitumor activity of TRAIL—suppression of metastases through natural killer (NK) cell regulation. They found that treatment with the TRAIL inducer, ONC201, resulted in tumor regression and prevented metastases in vivo. ONC201 treatment led to increased PD-L1-positive T cells and NK cells in the mouse tumor microenvironment, and increased circulating TRAIL-secreting NK cells in patient samples. NK cells were necessary for antitumor response. Finally, they demonstrated that the combination of ONC201 and an anti-PD-1 agent was more efficacious than anti-PD-1 monotherapy.
Expert Commentary: These studies describe a novel mechanism of action for ONC201, which is already in clinical trials. Thus, the combination of anti-PD-1 and ONC201 could rapidly be investigated in the clinic.
NFκB in KRAS Mutant Lung Cancer
Approximately 30 to 40% of lung adenocarcinomas (LADC) diagnosed in Europe and North America harbor KRAS mutations. Mutant KRAS was recently shown to interact with IKKs, key intermediates in NFκB signaling, to promote survival, stemness, and drug resistance in LADC. Vreka and colleagues scrutinized the role of IKKα and IKKβ in KRAS-mutant LADCs induced by urethane in combination with respiratory epithelial expression of oncogenic KRASG12D. In mouse models of tobacco carcinogen- and oncogenic KRASG12D-generated LADC, IKKα was essential for disease initiation and progression. Moreover, IKKα selectively advanced cellular proliferation in the context of mutant KRAS and was also highly expressed in human LADC.
Expert Commentary: The authors confirm a requirement for IKKα in KRAS-driven LADC, implicate IKKα as a KRAS nononcogene addiction partner, and show that targeting IKKα may block LADC, an aggressive and therapeutically resistant cancer.
Phosphoprotein Signaling across Medulloblastoma Subgroups
To discern protein signaling effectors, Zomerman and colleagues profiled phosphorylation of 285 synthetic peptides from 50 primary medulloblastomas. They observed a MYC-like cluster enriched for responses to DNA damage and external stimuli, and p53, apoptotic, and neuronal signaling. A second cluster was enriched for cell-cycle transition and G-protein-coupled receptor signaling. The MYC-like cluster consisted of SHH and half of Group 3 tumors with high MYC levels, while cluster 2 comprised the remaining Group 3s with lower MYC and Group 4s. In immortalized epithelial cells, MYC/MYCN overexpression and a TP53 mutant/null had protein signaling states similar to the MYC-like cluster. Finally, the DNA-damage response/p53 signaling abnormalities in the MYC-like cluster may respond to WEE1 and ATR inhibition that exacerbate DNA replication stress.
Expert Commentary: This study shows that the two highest risk groups of medulloblastoma (TP53 mutant SHH and MYC-amplified Group 3s) share similar signaling networks, suggesting a common approach of targeting replication stress.
Zomerman WW, Plasschaert SLA, Conroy S, Scherpen FJ, Meeuwsen-de Boer TGJ, Lourens HJ, et al. Identification of two protein-signaling states delineating transcriptionally heterogeneous human medulloblastoma. Cell Rep 2018;22:3206–16.
Note: Breaking Insights 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.