Epidermal growth factor receptor–Kirsten rat sarcoma viral oncogene homolog G12D signaling axis (EGFR–KRAS G12D axis) (EGFR–KRAS G12D axis)

The Epidermal growth factor receptor–Kirsten rat sarcoma viral oncogene homolog G12D (EGFR–KRAS G12D) signaling axis is a critical oncogenic pathway where EGFR serves as a key upstream regulator and a primary feedback bypass mechanism for the KRAS G12D mutant protein [1, 3]. In malignancies such as pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), the KRAS G12D mutation drives constitutive signaling through the MAPK/ERK and PI3K/AKT pathways, promoting uncontrolled cell proliferation and survival [8, 10]. Preclinical studies have demonstrated that selective inhibition of KRAS G12D often triggers a compensatory feedback loop involving the activation of EGFR, which reactivates downstream signaling via wild-type RAS isoforms (H-RAS and N-RAS), thereby limiting the efficacy of KRAS-targeted monotherapy [1, 3]. Consequently, the simultaneous targeting of both EGFR and KRAS G12D—either through combination regimens using KRAS G12D inhibitors (e.g., MRTX1133) and EGFR inhibitors (e.g., Cetuximab) or through novel modalities like EGFR-targeted KRAS G12D antibody-drug conjugates (e.g., JAB-BX600)—is a major therapeutic strategy aimed at overcoming adaptive resistance [5, 11]. This axis represents a significant focus in precision oncology for managing RAS-mutant tumors that have historically been difficult to treat with single-agent therapies [8, 10]. Sources: [1] Oncogene (2023) 42:1620-1633; [3] PMC610181928; [5] Jacobio Pharma Pipeline (2025); [8] PMC10741234 (2025); [10] Mini-review on KRAS G12D (2025); [11] Jacobio Pharma Press Release (2025).

Other names

EGFR-KRAS G12D pathwayEGFR-KRAS G12D feedback loopEGFR/wild-type RAS signaling axisEGFR-KRAS G12D co-dependency

The mechanism of action involves the simultaneous or sequential inhibition of the KRAS G12D mutant protein and its upstream activator, EGFR. By blocking KRAS G12D, the primary oncogenic driver is suppressed; however, to prevent the adaptive resistance caused by EGFR-mediated reactivation of the RAS-MAPK pathway (often through wild-type RAS isoforms like H-RAS and N-RAS), an EGFR inhibitor is added [1, 3]. This dual blockade ensures more complete and sustained suppression of downstream signaling, leading to enhanced apoptosis and growth arrest in tumor cells harboring the G12D mutation [3, 8].