Abstract 77: Therapeutic potential of ERK inhibitors in overcoming acquired resistance to third generation EGFR tyrosine kinase inhibitors

Targeting epidermal growth factor receptor (EGFR) activating mutations, 90% of which present as an exon 19 deletion (Del19) or exon 21 point mutation (L858R), with first and second generation EGFR tyrosine kinase inhibitors (EGFR-TKIs; e.g., erlotinib and afatinib) and T790M resistant mutation with third generation EGFR-TKIs (e.g., AZD9291 or osimertinib) has provided significant clinical benefit in patients with non-small cell lung cancer (NSCLC) carrying these mutations. AZD9291 selectively and irreversibly inhibits EGFR activating and T790M mutants while sparing wild-type EGFR. It is now an approved therapeutic option for NSCLC patients with activating EGFR mutations (first-line) or those who have become resistant to the 1st generation EGFR-TKIs through the T790M mutation (second-line). Unfortunately, all patients eventually relapsed and developed resistance to AZD9291 treatment, limiting the long-term benefit of this targeted therapy. Hence the effective strategies that can overcome the resistance are urgently needed in the clinic. We have recently demonstrated that modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and loss of MEK/ERK-mediated Bim and Mcl-1 modulation is a key mechanism accounting for development of acquired resistance to AZD9291. Accordingly we have suggested that inhibition of the MEK/ERK signaling, which enforces Mcl-1 reduction and Bim elevation, might lower the threshold of AZD9291-resistant cells to re-respond to AZD9291 for undergoing apoptosis and achieve the goal of overcoming acquired resistance. Indeed, the combination of AZD9291 with a MEK inhibitor effectively decreases cell survival with enhanced apoptosis irrespectively of resistant mechanisms and inhibited the growth of AZD9291-resistant xenografts in vivo as we recently reported. In the current study, we further show that the combination of AZD9291 with an ERK inhibitor synergistically decreased the survival of AZD9291-resistance cell lines with enhanced induction of apoptosis. Moreover, the combination of a MEK or ERK inhibitor with a first (e.g., erlotinib) or second (e.g., afatinib) generation EGFR-TKIs also very effectively decreased the survival of AZD9291-resistance cell lines although these cell lines were cross-resistant to first and second generation EGFR-TKIs. Therefore, our results have provided additional evidence supporting the notion that co-targeting the MEK/ERK signaling is an effective strategy for overcoming AZD9291 acquired resistance irrespectively of the underlying resistance mechanisms. Our findings warrant further investigation of this therapeutic strategy to overcome AZD9291 resistance in the clinic. (This study was supported by the NIH/NCI R01 CA223220 and Winship lung cancer pilot award) Citation Format: Yiting Li, Guoqing Qian, Taofeek K. Owonikoko, Suresh S. Ramalingam, Shi-Yong Sun. Therapeutic potential of ERK inhibitors in overcoming acquired resistance to third generation EGFR tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 77.