Depleting receptor tyrosine kinases EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and panitumumab, are valuable therapeutics for colorectal cancer (CRC), but resistance to these inhibitors is common. The reason for such resistance is not well understood, which hampers development of better therapeutic strategies. Although activating mutations in KRAS, BRAF and PIK3CA are considered major drivers of CRC resistance to EGFR inhibitors, therapeutic targeting of these drug resistance drivers has not produced substantial clinical benefit. METHODS: We exploited cell lines and mouse tumor models (cell line xenografts and patient derived xenografts) for experiments of genetic and pharmacologic depletion of EGFR and/or its family member HER2, including EGFR mutants, inhibition of EGFR ligand shedding, and biochemical analysis of signaling proteins, to delineate the mechanism of CRC resistance to EGFR inhibitors and to assess the therapeutic activity of PEPD(G278D), which is a recombinant human protein that induces the degradation of both EGFR and HER2. RESULTS: The sensitivity of CRC cells to cetuximab and panitumumab correlates with the ability of these drugs to induce EGFR downregulation. PEPD(G278D) strongly inhibits oncogenic signaling and growth of CRC cells by causing profound depletion of EGFR and HER2, regardless of activating mutations of KRAS, BRAF and PIK3CA. siRNA knockdown of EGFR or HER2 also inhibits CRC cells resistant to EGFR inhibitors. Tumors harboring mutated KRAS, BRAF and/or PIK3CA also overexpress EGFR ligands, further suggesting that EGFR signaling remains important to the tumors. While excessive tumor-generated high-affinity EGFR ligands block target engagement by PEPD(G278D), aderbasib, an inhibitor of ADAM10 and ADAM17, enables PEPD(G278D) to exert strong antitumor activity by inhibiting ligand shedding. Moreover, adding fluorouracil, which is commonly used in CRC treatment, to the combination of PEPD(G278D) and aderbasib further enhances tumor inhibition. CONCLUSIONS: Our study shows that CRC resistance to EGFR inhibitors results primarily from the inability of the inhibitors to downregulate their target and that a PEPD(G278D)-based combination treatment overcomes the resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02389-z.