Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations

Abstract

Recent clinical data indicates that the emergence of mutant drug-resistant kinase alleles may be particularly relevant for targeted kinase inhibitors. In order to explore how different classes of targeted therapies impact upon resistance mutations, we performed EGFR (epidermal-growth-factor receptor) resistance mutation screens with erlotinib, lapatinib and CI-1033. Distinct mutation spectra were generated with each inhibitor and were reflective of their respective mechanisms of action. Lapatinib yielded the widest variety of mutations, whereas mutational variability was lower in the erlotinib and CI-1033 screens. Lapatinib was uniquely sensitive to mutations of residues located deep within the selectivity pocket, whereas mutation of either Gly(796) or Cys(797) resulted in a dramatic loss of CI-1033 potency. The clinically observed T790M mutation was common to all inhibitors, but occurred with varying frequencies. Importantly, the presence of C797S with T790M in the same EGFR allele conferred complete resistance to erlotinib, lapatinib and CI-1033. The combination of erlotinib and CI-1033 effectively reduced the number of drug-resistant clones, suggesting a possible clinical strategy to overcome drug resistance. Interestingly, our results also indicate that co-expression of ErbB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) has an impact upon the EGFR resistance mutations obtained, suggesting that ErbB2 may play an active role in the acquisition of drug-resistant mutations.

Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

“…The level of proteins in blood available to bind lapatinib plays another role by changing the free drug fraction 17,18 . Lapatinib insensitivity can also be caused by intratumoral signal pathway changes leading to an overwhelming of its inhibitory effect [57][58][59][60][61][62] .…”

“…However, some BCs do not respond or develop resistance to lapatinib too (e.g. tumors with HER2 tyrosine kinase domain mutations; HER1 tyrosine kinase domain mutations; PIK3CA mutation, PTEN loss, AXL overexpression, RelA activation) [57][58][59][60][61][62] . Enhanced estrogen signaling described in vitro may also be a route for increased tumor cell survival on lapatinib treatment.…”

Phase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid Tumors

“…However, because molecular heterogeneity among and within tumors, their efficacy is restricted to a small subset of patients (2). The efficacy of RTK inhibitors is also limited by drug resistance that frequently emerges following treatment (3,4). Several strategies have been proposed to overcome the limited activity of, and acquired resistance to RTK inhibitors.…”

“…3 South Texas Oncology Hematology (STOH), San Antonio, Texas. 4 Curis, Inc., Lexington, Massachusetts.…”

Synthesis and Biological Evaluation of 1-(2-Aminophenyl)-3-arylurea Derivatives as Potential EphA2 and HDAC Dual Inhibitors

“…22) HDAC inhibitors have been shown to synergize with other agents, including RTK inhibitors, to suppress proliferation and induce apoptosis in tumor cells. 23,24) This evidence suggests that simultaneous EphA2 activation and HDAC inhibition could be a promising approach in cancer therapy. Here, compound N-(4-(3-(2-aminophenyl) ureido) phenyl)-4-methylbenzamide (5e) was disclosed to inhibit EphA2 and HDAC based on the virtual screening.…”