By identifying the alkaline pHi as an activator of AMPK–mTORC2 signaling that attenuates apoptosis caused by growth factor withdrawal, our work suggests that the AMPK–mTORC2 axis may drive tumorigenesis in response to dysregulated pH dynamics by enabling growth factor–deprived, nutrient-deprived, and oxygen-deprived cancer cells at the core of a growing tumor to survive. The gene discussed is PRKAA1; the disease is cancer.