Thus, therapeutic resistance can be caused for instance by constitutive PI3K-AKT signaling that hyperactivates mTOR and therefore inhibits autophagy, which is encountered in many cancer cells; this is often due to mutations in PI3K itsself or other upstream signaling factors, loss of the tumor suppressor genes PTEN (phosphatase and tensin homolog) and ARHI, or by AKT overexpression [155,156,157,158]. Here, PTEN is linked to cancer.