PIK3CA and neoplasm: One of the main mechanisms revealed is the EGFR and the PI3K/AKT/mTOR pathway bypass activations.643 In the case of the HER2-inhibitor lapatinib, a calcium-dependent activation of the RelA (NF-kB) pathway has been observed in resistant cells.684 In the case of GIST, the implication of the sphingophospholipid metabolic pathway is suggested to cause resistance to the non-selective inhibitor imatinib.685 The number of specific receptors on the surface of tumor cells also influences sensitivity to RTK-inhibitors.