Mcl-1 is a Dominant Bcl-2 Oncoprotein in Breast Cancer
In the current study, Williams and colleagues develop a proximity ligation assay (PLA) to measure the activity of Bcl-2 family members in situ. The team assesses Bcl-2 family inhibition in estrogen receptor-positive (ER+) breast cancers, finding poor response to ABT-263, a dual Bcl-2/Bcl-xL inhibitor, due to acute upregulation of a related factor, Mcl-1. Breast cancers from the clinic were determined to express higher transcript levels of the MCL1 gene, and were more frequently amplified, than other Bcl-2 members. Mcl-1 knockdown increases tumor cell death alone and in combination with ABT-263. Importantly, MCL1 transcript levels predict sensitivity to Bcl-2/Bcl-xL blockade, a timely finding as inhibitors of the Bcl-2 family enter clinical trials in breast cancer.
CDK4/6i-induced Stromal Senescence Aids Melanoma
Cyclin-dependent kinase 4/6 inhibitors (CDKi's) block tumor proliferation by mimicking p16INK4a function and are the subject of ongoing clinical trials. Similar to prolonged endogenous p16INK4a expression, extended CDK4/6i treatment promotes senescence in normal, proliferating cell lines. Senescence is associated with decreased regenerative capacity, age-related disease and cytokine secretion (i.e., SASP). Here, Guan and colleagues establish that primary fibroblasts, coaxed into senescence by prolonged CDK4/6i treatment, produce a robust cytokine profile/SASP that limits the anti-tumor immune response and promotes melanoma growth in immunocompetent models. These data reveal that the effects of CDK4/6i treatment on primary cells hinders therapeutic efficacy and promotes long-term, gerontogenic consequences.
PI3K/mTOR Inhibition in Colorectal Cancer with APC and PIK3CA Mutations
Mutations in the PIK3CA gene, activating phosphoinositide-3 kinase (PI3K), are commonly observed in colorectal cancer. Unfortunately, attempts at targeting this signaling cascade in colon cancer have resulted in significant therapeutic resistance. To investigate therapeutic strategies for this subtype, APC and PIK3CA mutant genetically engineered mice and spheroid cultures were generated. Using these model systems, dual PI3K/mTOR inhibition was discovered to induce treatment responses in spheroid cultures and in vivo. These results identify dual PI3K/mTOR inhibitors as a potential treatment strategy for patients with PIK3CA mutant colorectal cancer and deserve further clinical investigation.
Let-7a miRNA Regulates PARP1 Expression
Previously we have shown that HER2+ breast cancers are susceptible to PARP inhibition (PARPi) independent of a DNA repair defect, and express elevated levels of PARP1. Now, Wielgos and colleagues discover that HER2 regulates PARP1 expression through suppression of the let-7a miRNA. Mechanistically, let-7a regulates PARP1 at the PARP1 3′-UTR. In human breast tumors, HER2 status correlates with high PARP1 protein and low let-7a. Lastly, introducing let-7a into HER2+ breast cancer cells induces cytotoxicity to a similar extent as the PARP inhibitor veliparib. Collectively, these findings demonstrate the potential of let-7a as a therapeutic strategy to target PARP1, and that baseline levels of let-7a and PARP1 are prospective biomarkers for PARPi sensitivity.
- ©2017 American Association for Cancer Research.