Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer

Abstract

EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.

Resistance May Not Be Futile: microRNA Biomarkers for Chemoresistance and Potential Therapeutics

“…One common effective class of agents against aberrant expression of EGFR is the EGFR tyrosine kinase inhibitor (TKI; refs. 37,38). TKIs can be dramatically effective for advanced NSCLC patients whose tumor harbors an EGFR mutation associated with drug sensitivity (e.g., G719X, exon 19 deletion, and L858R): 70% will experience tumor regression when initially treated (37), but acquired resistance, attributed largely to an increased selection in tumor cells for TKIresistant EGFR mutations, is quite common (37,38).…”

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

“…Although afatinib showed clinical efficacy as single agent in the TKIs-na€ ve setting (17), the response rates in acquired resistance setting were below 10% (18). In xenograft models of TKI-resistant tumors harboring T790M mutation, dual inhibition of EGFR with afatinib plus cetuximab induced encouraging tumor shrinkage (19). This combination regimen has demonstrated an augmented response rate of 29% for TKI-resistant EGFRmutant NSCLC patients in a recent clinical trial (20).…”

Successful treatment of a patient with Li–Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib

“…22 Accumulating evidence has demonstrated cross-talk between HER family members in the development of acquired resistance to EGFR-TKI therapy. 26,27 HER2 overexpression also can confer resistance to EGFR-TKIs in cell line models and the HER2 gene was found to be amplified in a significant fraction of both murine and human tumors with acquired resistance to erlotinib. As noted earlier, re-biopsy of such a unique tumor upon progression could provide further clues as to the contribution of the two synchronous oncogenic pathways to acquired resistance.…”