PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Abstract

Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale lossof-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.

The emerging role and targetability of the TCA cycle in cancer metabolism

“…Allen et al conducted a focused siRNA screen on TCA cycle enzymes, and found that many cancer cells highly depend on OGDH (the E1 component of KGDHC) for growth and survival (Allen et al, 2016 ). A recent study by Ilic et al demonstrated that cancer cells harboring oncogenic PI3K mutations require all three components of KGDHC, OGDH in particular, for proliferation (Ilic et al, 2017 ). These findings support the rationale to target KGDHC for cancer treatment.…”

Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer

“…It is well established that hyperactive PI3K/Akt signaling contributes to increased glycolytic rate, and recent studies have identified dependencies on specific metabolic enzymes that, when perturbed, impact glycolytic flux and consequently cancer cell viability ( 35 ). Notably, PIK3CA mutant cancer cell lines have elevated 2-oxoglutarate dehydrogenase (OGDH) activity, and inhibition of this enzyme leads to reduced tumor growth in vivo ( 35 ). The sensitivity to OGDH inhibition can be explained by the observed decrease in the NAD + /NADH ratio following accumulation of 2-oxoglutarate, thus limiting the available NAD + needed for glycolysis ( 35 ).…”

“…Notably, PIK3CA mutant cancer cell lines have elevated 2-oxoglutarate dehydrogenase (OGDH) activity, and inhibition of this enzyme leads to reduced tumor growth in vivo ( 35 ). The sensitivity to OGDH inhibition can be explained by the observed decrease in the NAD + /NADH ratio following accumulation of 2-oxoglutarate, thus limiting the available NAD + needed for glycolysis ( 35 ). Interestingly, OGDH is a potent source of ROS and this, together with the need to maintain a stable NAD + /NADH ratio, suggests that maintaining redox homeostasis is essential for the proliferation of PIK3CA mutant tumors ( 35 , 36 ).…”

“…The sensitivity to OGDH inhibition can be explained by the observed decrease in the NAD + /NADH ratio following accumulation of 2-oxoglutarate, thus limiting the available NAD + needed for glycolysis ( 35 ). Interestingly, OGDH is a potent source of ROS and this, together with the need to maintain a stable NAD + /NADH ratio, suggests that maintaining redox homeostasis is essential for the proliferation of PIK3CA mutant tumors ( 35 , 36 ). Another important ROS-generating metabolic pathway that is regulated by PI3K/Akt signaling is the production of prostaglandins (PGE 2 ) from arachidonic acid by the cyclooxegenases COX-1 and COX-2 ( 37 ).…”

Coessentiality and cofunctionality: a network approach to learning genetic vulnerabilities from cancer cell line fitness screens

“…This complex is strongly essential in five Her2+ cell lines but nonessential in 8 others, suggesting the presence of further metabolic subtypes within the recognized Her2+ subtype [26]. A recent report indicates that dependency on αKGDH is driven by PIK3CA mutations [27]. However, the differential sensitivity to perturbation in our network is not correlated with PIK3CA mutation status: 3/5 sensitive cell lines and 4/8 insensitive cell lines carry oncogenic PIK3CA mutations (P=0.59, Fisher's exact test).…”