Dexamethasone blocks estrogen-induced apoptosis
Fan et al. Page 1684
The endoplasmic reticulum stress sensor PERK/NF-κB/TNFα axis has been identified to be critical for estrogen (E2)-induced apoptosis in long-term E2-deprived (LTED) breast cancer cells. Fan and colleagues found that both E2 and the synthetic glucocorticoid dexamethasone (Dex) upregulated inflammatory factors such as fatty acid desaturase 1 (FADS1) and interleukin-6 (IL-6). Unlike E2, Dex selectively and constantly suppressed TNFα expression. A mechanistic finding was that activated glucocorticoid receptor (GR) preferentially suppressed NF-κB DNA-binding activity, which prevented activation of NF-κB-dependent TNFα and ultimately resulted in complete blockade of E2-induced apoptosis. These findings have important clinical implications for the conservative therapeutic application of glucocorticoids in treatment of advanced aromatase inhibitor-resistant breast cancer.
Selective cytotoxicity of RITA analogs
Peyser et al. Page 1765
The preclinical antitumor agent RITA was dropped from development at NCI due to pulmonary toxicity in animal models. Laboratory data support activation of RITA analogs by phenol sulfotransferase. Peyser and colleagues demonstrate a method to quantify high selectivity in the NCI-60 cell screen, and show that specific modifications to the chemical scaffold narrow its broad scale cytotoxicity. Quantum mechanics calculations indicate that the improved designs produce stabilized, sulfonated metabolites that exhibit a profound increase in cytotoxic selectivity. Three of these new hyperselective analogs display in vivo efficacy, suggesting a potential return to drug development for this promising chemotype.
TTK inhibition and lung cancer
Zheng et al. Page 1775
Tyrosine Threonine Kinase (TTK/Mps1) is a key component that maintains genomic integrity in the spindle assembly checkpoint. TTK inhibition is hypothesized by Zheng and colleagues to cause genomic instability and cell death. CFI-402257 is a selective and potent TTK inhibitor that exerts marked antineoplastic effects against murine and human lung cancer cell lines. It also represses tumorigenicity of xenograft and syngeneic lung cancers by promoting aneuploidy and apoptosis. Intriguingly, CFI-402257 treatment enhanced MAp. signaling and MAPK antagonism augmented its anticancer actions. Future work should determine if TTK antagonism alone or with a MAPK inhibitor has activity in the cancer clinic.
Modeling lung cancer subtype-selective drug sensitivities
Talwelkar et al. Page 1863
Treatment of KRAS mutant lung cancer is challenged by intrinsic and adaptive functional heterogeneity. Talwelkar and colleagues asked if tumor-selective signaling plasticity and its relation to drug sensitivity can be investigated ex vivo. Analyses were performed in primary KrasG12D/+;Lkb1fl/fl (KL) adenosquamous carcinoma or adenocarcinoma cultures or KrasG12D/+;p53fl/fl (KP) adenocarcinoma cultures. KL culture-selective adaptive ERBB signaling following MEKi was detected, and response to MEKi was exacerbated by pan-ERBBi. This KL-selective pan-ERBBi sensitivity was validated in vivo. In contrast, adenocarcinoma cultures of both genotypes showed adaptive FGFR signaling, and combinatorial MEKi and FGFRi sensitivity. Thus, ex vivo analysis exposes tumor-selective drug sensitivities and functionally stratifies Kras mutant lung cancers.