Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKI) have become the first line treatment for patients with EGFR mutated non-small cell lung cancer (NSCLC) as a result of multiple clinical trials demonstrating superior response and less toxicity as compared to conventional cytotoxic agents. However, despite the clinical experience among nearly two decades, it is well known that EGFR-TKI monotherapy cannot cure EGFR mutation-positive lung cancer patients due to the occurrence of drug resistance. While dramatic initial tumor shrinkage is shown in most patients with EGFR-TKI treatment, therapeutic resistance is often observed in 1-2 years. This is likely caused by the outgrowth of rare pre-existing resistant clones and/or small fraction of drug tolerant persister cells (DTPs) which survive and acquire resistance to EGFR-TKIs. Several previous studies have clarified the acquired resistance mechanisms to EGFR-TKIs, but little is known how the DTPs survive during the initial phase of drug exposure and rapidly adapt to EGFR-TKIs. Utilizing the genome wide CRISPR/Cas9 screening, we have previously reported that DTPs were capable to exploit endoplasmic reticulum stress to survive EGFR-TKI exposure (Terai, et al, Cancer Research 2018). Further analysis of this data identified multiple genes which could affect the initial drug response to EGFR-TKIs, including the scaffold protein coding gene, SHOC2. In our present study we focused on this unique protein and revealed its critical function as a modulator of drug response to EGFR-TKIs in lung cancer cells. We confirmed that depletion/overexpression of SHOC2 in PC9 cells, an EGFR-dependent NSCLC cell line, renders the cells sensitive/resistant to all 1st to 3rd generation EGFR-TKIs. We have also confirmed similar findings with another EGFR dependent NSCLC cell line named H1975. Reduction of phosphorylation levels of ERK1/2 induced by EGFR-TKIs were stronger in PC9 or H1975 cells with SHOC2 knockout, indicating that SHOC2 can facilitate ERK1/2 reactivation during EGFR-TKI treatment. The above data indicate that SHOC2 is essential for DTPs and its function is correlated with MAPK-ERK pathway activity. Celastrol, a candidate SHOC2 inhibitor, inhibited the emergence of DTPs and synergized with EGFR-TKIs. Additionally, we showed that SHOC2 depletion enhanced the growth inhibitory effect of osimertinib in vivo. Lastly, we confirmed the increased expression of SHOC2 in clinical human samples which experienced EGFR-TKI failure. Our findings could offer a new treatment strategy for NSCLC patients with EGFR mutation leading to the increase of the degree and duration of EGFR TKIs response.

Citation Format: Hideki Terai, Junko Hamamoto, Tadashi Manabe, Katsura Emoto, Takeshi Masuda, Satoshi Kuronuma, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Sohei Nakayama, Ichiro Kawada, Yusuke Suzuki, Osamu Takeuchi, Yukio Suzuki, Sumio Ohtsuki, Hiroyuki Yasuda, Kenzo Soejima, Koichi Fukunaga. SHOC2 is a critical modulator of the sensitivity to EGFR-TKI in non-small cell lung cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3081.