Maganti, S. | bioRxiv Science

bioRxiv2022

Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma

In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Despite this established dependency, the targeting of specific enzymes involved in glutamine metabolism is yet to yield any clinical benefit. Here, we have examined the therapeutic potential of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism. We found that DON treatment significantly blocks PDAC tumor growth and attenuates metastasis. Interestingly, we link the effectiveness of DON in PDAC to asparagine (Asn) metabolism. By inhibiting asparagine synthetase (ASNS), DON significantly reduces intracellular Asn production and Asn supplementation rescues the anti-proliferative effects of DON. We discern that PDAC cells upregulate expression of ASNS as a metabolic adaptation and that modulating ASNS levels can impact DON efficacy. Strikingly, in patient-derived organoids, DON responsiveness is inversely correlated with ASNS expression, a feature that is not observed for other metabolic enzymes targeted by DON. We find that treatment with L-asparaginase (ASNase), an enzyme that catabolizes free Asn, synergizes with DON to impact the viability of PDAC cells. Finally, we identify that a combination therapy of DON and ASNase has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of co-targeting adaptive responses to control PDAC progression.

cancer biology↗

bioRxiv2022

A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Anti-apoptotic Protein in Kidney Cancer

Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institutes Achilles shRNA screening dataset, we mined for targetable dependencies by cell lineage. Our studies identified a strong dependency on BCL2L1, which encodes the BCL-XL anti-apoptotic protein, in a subset of kidney cancer cells. Genetic and pharmacological inactivation of BCL-XL, but not the related anti-apoptotic proteins BCL-2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Neither BCL-XL levels (absolute or normalized to BCL-2) nor the status of the VHL gene, which is frequently mutated in kidney cancer, predicted BCL-XL dependence. Transcriptional profiling, however, identified a BCL-XL dependency mRNA signature, which included elevated mesenchymal gene expression in BCL-XL dependent cells. Promoting mesenchymal transition increased BCL-XL dependence; whereas, conversion to a more differentiated state overcame BCL-XL dependence in kidney cancer cells. The BCL-XL dependency mRNA signature was observed in almost a third of human clear cell Renal Cell Carcinomas (ccRCCs), which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed anti-tumor efficacy in vivo. Altogether, our studies uncovered an unexpected link between cancer cell state and dependence on the anti-apoptotic BCL-XL protein and justify further testing on BCL-XL blockade as a potential way to target a clinically aggressive subset of human kidney cancers. One Sentence SummaryCell state, but not pVHL and/or HIF status, defines the dependency of kidney cancer cells on the BCL-XL anti-apoptotic protein.

cancer biology↗