MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor–mutant lung cancers

Abstract

BACKGROUND: The majority of patients with non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations respond well to osimertinib (AZD9291), a third-generation, mutation-selective EGFR inhibitor. The current study focuses on determining whether targeting MEK/ERK signaling prevents or delays the development of acquired resistance to osimertinib. METHODS: Drug effects on cell survival were determined by measuring cell number alterations. Apoptosis was assessed with flow cytometry for the detection of annexin V-positive cells and with Western blotting for protein cleavage. Alterations of proteins in cells were detected with Western blotting. Drug effects on delaying the emergence of osimertinib resistance were evaluated with colony formation in vitro and xenografts in nude mice in vivo. RESULTS: Osimertinib combined with an MEK or ERK inhibitor synergistically decreased cell survival with enhanced induction of apoptosis in EGFR-mutant NSCLC cells but not in EGFR wild-type NSCLC cells. These combinations were also very effective in killing cell clones with primary intrinsic resistance to osimertinib. Continuous and intermittent pharmacologic inhibition of MEK/ERK signaling delayed the emergence of osimertinib resistance both in vitro and in vivo. CONCLUSIONS: These results provide strong preclinical evidence in support of targeting MEK/ERK signaling as a strategy for delaying or preventing acquired resistance to osimertinib in the clinic to improve the long-term therapeutic efficacy of osimertinib. From a clinical standpoint, the data support the evaluation of an intermittent treatment schedule of osimertinib in combination with an MEK or ERK inhibitor in patients with EGFR-mutated NSCLC.

Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

“…Concurrent and intermittent (two-weeks osimertinib followed by two-weeks combination with trametinib or four-weeks osimertinib followed by two-weeks combination with trametinib) application of trametinib with osimertinib substantially retarded the development of osimertinib resistance both in vitro and in vivo. 43 It deserves mentioning that we observed some mice without detectable tumors in each combination treatment group; this collectively accounted for a cure rate of 27.8% (5 of 18 mice in total). 43 This suggests that some patients may achieve long-term remission with these combination treatments and thus is clinically meaningful.…”

“…ERK reactivation also occurred on EGFR-mutant NSCLC cells exposed to osimertinib. 42 , 43 Osimertinib plus a MEK inhibitor such as trametinib-enhanced induction of apoptosis in different EGFR-mutant NSCLC cell lines and significantly delayed the emergence of acquired resistance to osimertinib as we recently demonstrated. 43 Another related aspect is that osimertinib lost its capacity to inhibit MEK/ERK signaling in different cell lines resistant to osimertinib evidenced by limited inhibitory effects on ERK phosphorylation as documented in several studies.…”

“… 42 , 43 Osimertinib plus a MEK inhibitor such as trametinib-enhanced induction of apoptosis in different EGFR-mutant NSCLC cell lines and significantly delayed the emergence of acquired resistance to osimertinib as we recently demonstrated. 43 Another related aspect is that osimertinib lost its capacity to inhibit MEK/ERK signaling in different cell lines resistant to osimertinib evidenced by limited inhibitory effects on ERK phosphorylation as documented in several studies. 20 , 42 , 44 This mechanism may also contribute to the acquired resistance to osimertinib and other third-generation EGFR-TKIs since co-targeting MEK or ERK can efficiently sensitize osimertinib-resistant cells and tumors to osimertinib as discussed below.…”

“…Our recent study has also shown that osimertinib combined with a MEK or ERK inhibitor exerts similar activity. 43 Osimertinib synergized with a MEK (eg, trametinib) or ERK (eg, VRT-752271) inhibitor in decreasing cell survival and enhancing induction of apoptosis in EGFR-mutant NSCLC cells, but not in NSCLC cells with WT EGFR. These combinations very effectively killed several clones that were intrinsically resistant to osimertinib via enhanced induction of apoptosis.…”

ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

“…More than 35% of all cancer deaths are from lung cancer [3]. In recent years, many targeted therapies, such as anaplastic lymphoma kinase (ALK) [4], EGFR [5], ROS1 [6], RET [7], HER2 [8], and MEK [9], have become available for advanced lung cancer, and more are in development [10]. Although there are many means of treating lung cancer, no speci c drugs have been found so far [11].…”