Phosphoinositide Protein Kinase PDPK1 in Multiple Myeloma
Chinen and colleagues identify a serine threonine kinase, 3-phosphoinositide-dependent protein kinase 1 (PDPK1), expressed in several multiple myeloma cell lines. PDPK1 was found to regulate RSK2, AKT, c-MYC, IRF4, and Cyclin Ds, molecules important for myeloma. Additionally, PDPK1 inhibition caused inhibition of growth and induction of apoptosis and enhanced the in vitro cytotoxic effects of antimyeloma agents. Importantly, PDPK1 was active in cells from 90% of patients, with patients negative for PDPK1 activity showing improved prognosis. Thus, PDPK1 activation might accelerate disease progression and resistance to treatment. In these contexts, the authors have identified a potentially common targetable molecule for multiple myeloma regardless of cytogenetic/molecular profiles of this heterogeneous hematologic malignancy.
Mutations That Lend Therapeutic Insight into Esophageal Carcinoma
Characterization of esophageal squamous cell carcinoma has not previously identified avenues for targeted therapeutics. Gao and colleagues performed mutational profiling of 113 pairs of tumor and normal DNA from individuals of Chinese ancestry and identified a mutation frequency that was substantially lower than that of UV-exposed melanomas and smoking-related lung cancers. Importantly, frequent and recurrent mutations of histone modifier genes (EP300 and CREBBP) and Hippo pathway regulators (AJUBA and FAT-family of genes) were identified, findings that have prognostic and potentially therapeutic implications. This study begins to shed light on more rational ways of targeting an otherwise lethal malignancy.
Dependence on Mitochondrial Function Drives Relapse
Using a novel tetracycline inducible Kras oncogene-driven mouse model for pancreatic ductal adenocarcinoma (PDAC), Viale and colleagues found that murine PDACs regressed rapidly in response to turning off transcription of Kras. PDACs reappeared 4 to 5 months later, however, arising from residual surviving cancer cells. Isolated surviving cancer cells expressed markers and showed properties characteristic of tumor stem cells. Further, surviving cancer cells showed increased dependence on mitochondrial function and oxidative phosphorylation, as well as autophagy and lysosomal activities. Consistent with this increased dependence on mitochondrial function for cellular energy, PDAC-derived spheres ex vivo and PDACs in vivo showed decreased recurrence in response to inhibitors of oxidative phosphorylation. Similar sensitivity to reduced oxidative phosphorylation was observed in human PDACs, cultured as spheres ex vivo, suggesting that inhibitors of this process might be combined with targeted therapy to block relapse.
CD19-Directed Therapy for Refractory Leukemia
The engineering of T cells to express chimeric antibodies that target tumor antigens (as shown in this “CAR-toon”) is revolutionizing outcomes for patients with highly refractory acute lymphoblastic leukemia. Maude and colleagues report a 90% objective and sustained response rate in children and adults with CD19+ leukemia. Remarkably, this study describes durable persistence of chimeric antigen receptor (CAR) T cells demonstrated by B-cell aplasia seen in all 19 patients with long-term remissions. None of these patients had a CD19+ relapse. The most significant toxicities involved cytokine-release syndrome with occasional self-limited neurologic toxic effects, some degree of which is likely necessary for efficacy. Mechanisms of resistance have not yet been elucidated but will be critical to our understanding of CD19-directed CAR T-cell therapy.
Cancer–Stroma Cross-talk
Boelens and colleagues demonstrate roles for exosomes and pattern recognition receptors in cancer–stroma cross-talk, identifying IFN-related DNA damage resistance signature genes (IRDSG) in therapy-resistant breast cancer. Compared with MDA-MB-231 breast cancer xenografts alone, admixing tumor cells with nontransformed human fibroblasts led to increased growth, therapy resistance, and expression of IRDSG. IRDSG expression depended on cancer cell expression of STAT1 and the pattern recognition receptor RIG-I (DDX58). Interestingly, exosome RNA containing the RIG-I ligand 5′-triphosphate RNA was necessary for RIG-I-dependent induction of IRDSG. While exposure to stromal-derived exosomes through a trans-well filter induced IRDSG, it did not mediate therapy resistance, with resistance dependent on transcription of NOTCH target genes through paracrine-activated STAT1 and juxtacrine-activated NOTCH3. This NOTCH response expands therapy-resistant breast cancer cells, and inhibition of this response helps prevent resistance in vivo.
A Function for TMPRSS2 in Prostate Cancer Metastasis
The promoter of the serine protease transmembrane protease, serine 2 (TMPRSS2) is commonly fused to other genes, such as ERG. Because TMPRSS2 is tightly regulated by androgen, the fused ERG transcription factor can strongly induce proliferation. Despite this knowledge, the function of TMPRSS2 to date has remained unknown. Lucas and colleagues now show that this serine protease is selectively upregulated in human prostate cancer and in mouse models. Loss-of-function experiments revealed that TMPRSS2 was required for prostate cancer dissemination and metastasis via epithelial–mesenchymal transition (EMT). The authors also identified hepatocyte growth factor (HGF) as the target of TMPRSS2 and report that increased expression of TMPRSS2 led to enhanced HGF/c-Met signaling, driving EMT. Finally, they identified a small molecule inhibitor of TMPRSS2 that can suppress EMT and metastatic functions. This elegant study answers a long-standing question about the normal and pathophysiologic role of TMPRSS2 in the prostate.
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.
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