“…Acquired resistance to KRAS G12C i monotherapy is thought to be mediated by multiple mechanisms 5,11,13,14,[19][20][21] , such as upstream bypass events including RTK activation 21 , KRAS G12C amplification 50 , activation of alternative signaling pathways including PI3K, mTOR, YAP-TEAD pathways, acquisition of low frequency secondary KRAS mutations that preclude compound binding (e.g. R68S, Y96C/D, H95D/Q/R) 13 , conversion of the G12C codon mutation, and additional activating KRAS mutations (G13D, Q61H) 15,36 .…”