Harnessing Cancer’s pH-Vulnerability to Identify an Optimal Two-Step Therapeutic Strategy

The initiation and development of cancer is associated with major metabolic alterations. An important aspect and often overlooked of cancer metabolism is the acidification of its extracellular environment and the concomitant alkalization of the cytoplasm, generating a reverse pH-gradient. Although much effort has been devoted to studying the consequences of extracellular acidification of cancer’s microenvironment, the role and importance of intracellular alkalization remains poorly understood. Here we provide for the first time a systems biology comprehensive understanding of how changes in intracellular pH (pHi) are coupled to network-wide cancer metabolic alterations, by integrating enzymatic pH-dependent activity profiles into human genome-scale metabolic models of cancer and normal cells. We show that lowering pHi renders cancer cells vulnerable for disruption and contributes to reversing its “Warburg” nature. This vulnerability is further exploited to identify optimal metabolic targets whose inhibition selectively kills cancer at low pHi. The results unravel an unprecedented role of intracellular pH in cancer metabolism and put forward a ground for novel combinatorial efficient therapy.