Abstract KRAS G12C inhibitors, such as sotorasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Clinical efficacy is achieved in NSCLC as a single agent and in CRC in combination with anti-EGFR monoclonal antibodies, however, secondary resistance impairs the effects of KRAS G12C blockade. In this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS-EGFR inhibition. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signalling by drug can be detected at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumour marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification became addicted to these agents and undergoes oncogene-induced senescence upon drug withdrawal. Accordingly, the KRAS G12C signal in circulating DNA from relapsed patients harbouring G12C amplification rapidly recedes upon treatment holiday. These data indicate that KRAS G12C amplification is a recurrent resistance mechanism to KRAS-EGFR co-inhibition and suggest a potential therapeutic vulnerability, whereby therapies that target this senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.