Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer

Abstract

Irreversible pyrimidine based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR activating and EGFR inhibitor resistant T790M mutations more potently than wild type EGFR. While this class of mutant selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFR T790M, prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002 induced apoptosis and inhibits the emergence of resistance in WZ4002 sensitive models known to acquire resistance via both T790M dependent and independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial co-targeting of EGFR and MEK could significantly impede the development of acquired resistance in mutant EGFR lung cancer.

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

“…Moreover, to address resistance via MET amplification recently a bispecific EGFR-cMET antibody was developed with very encouraging results in vitro and in vivo (47). Similarly, as mentioned above, different studies, presenting activation of RAS-MAPK pathway as mechanism of acquired resistance, provide results of a combination of third-generation TKI with a MEK inhibitor (13,31,43). Overall, these data support the use of a combination of EGFR-TKIs with an inhibitor of a different pathway (MET, MEK, IGFR, etc.)…”

Melanoma Therapeutic Strategies That Select Against Resistance by Exploiting MYC-Driven Evolutionary Convergence

“…In melanoma, the 'common effector' hypothesis is also consistent with the observation that BRAFi/MEKi-resistant tumors driven by diverse upstream signaling alterations exhibit highly recurrent transcriptional programs . Finally, this hypothesis is supported by recent data from our group and others demonstrating that distinct mechanisms of resistance to receptor tyrosine kinase inhibitors in lung and colorectal cancers converge on a single downstream signaling axis, the targeting of which can forestall resistance (Hrustanovic et al, 2015;Misale et al, 2015;Tricker et al, 2015).…”

Stratified Treatment in Lung Cancer

“…This complexity represents a growing challenge and combination therapies are tested to overcome resistance through multiple factors [29,31,32]. The heterogeneous nature of resistance makes tissue analysis by thorough genetic profiling indispensable to treatment decision-making.…”

“…Co-occurrance of EGFR T790M and other mechanisms such as amplification of MET and HER2 or the activation of the MEK/ERK pathway were found in subsets of patients [29,30,31,32,44]. Single agent treatment with third-generation EGFR TKIs seems to be insufficient in this setting [29,30,32,44,45].…”