Abstract
摘要:表皮生長因子受體 (EGFR)突變產生的肺腺癌腫瘤,雖然可以利用第一代小分子藥物(TKI)縮小腫瘤,病人仍會產生復發的抗藥性腫瘤。研究指出,抗藥性的主因是因為EGFR 的激酶結構區產生了T790M 的點突變,這個突變導致第一代小分子藥物和EGFR 的結合能力下降。第三代EGFR-TKI,AZD9291 和CO-1686,非可逆性的結合於EGFR 激酶結構區的C797 胺基酸上,可抑制不正常的EGFR活化,進而抑制對第一代TKI 產生抗藥性腫瘤的生長。最近臨床試驗結果顯示,EGFR 發生第三次C797S 的點突變會造成病人產生對第三代TKI 抗藥性的主因,占了40%的高比例。截至目前為止,當病人產生第三次突變後,我們就沒有更有效的標靶藥物可以抑制腫瘤生長。所以我們需要找到新穎藥物可以克服第三次突變所產生的抗藥性。在這個研究計畫中, 我們將利用對三突變L858R/T790M/C797S-EGFR 依賴性的Ba/F3 細胞做高通量藥物篩選,預期找到新的藥物克服抗藥性腫瘤生長。本計畫將聚焦四個重點來執行: (1) 利用高通量藥物篩選技術篩選抑制EGFR-L858R/T790M/C797S 活性的小分子藥物。(2) 確認這些藥物和EGFR 的結合位置。(3) 藉由修飾藥物官能基設計降低作用濃度和提高準確度的衍伸物。(4) 以動物實驗來驗證這些藥物是否抑制抗藥性腫瘤的生長。透過這個計畫的執行,我們期望我們可以得到新穎藥物克服肺癌病患因為EGFR-C797S 點突變造成的TKI 抗藥性。
Abstract: Lung cancer is the leading cause of cancer mortality worldwide, including the United States, mostdeveloped countries and Taiwan. Abnormal epidermal growth factor receptor (EGFR) signaling is the majordriver pathway in lung adenocarcinoma, which is the predominant subtype of lung cancer. The activatingmutation of EGFR may function as an oncogenic driver in more than 50% of Asian and 10-15% of Caucasianlung adenocarcinomas. Patients harboring activating EGFR mutants, most commonly L858R and Exon 19deletion, usually show good initial responses to EGFR-TKIs and survival improvement, but they eventuallydevelop disease progression after a median 12 months treatment. Acquired T790M mutation accounts for55-60% of these resistant cases. Other resistant mechanisms include the activation of alternative oncogenicpathways (c-Met, IGFR, HER3, Slug, AXL, HGF, PTEN and others) or small cell transformation. TheEGFR-TKI resistance poses a major clinical challenge in the treatment of lung adenocarcinoma, and thesecond-site acquired resistance mutation (along with T790M) in the kinase domain has been observed alower affinity to TKIs in more than 50% of patients. Of note, two of the third generation-EGFR TKIs(AZD9291 and CO-1686) had been approved by FDA that were effective against the kinase activity ofEGFR-T790M in lung adenocarcinoma cells through irreversibly cysteine modification on EGFR at C797site. However, the recent reports also indicated that EGFR at C797S mutation in kinase domain was found inmajority (40%) of resistance to third generation EGFR-TKI (AZD9291) in patients with EGFR-T790M.When patients with resistant triple mutant-EGFR occurred, currently there is no available effective targetingdrug to suppress the abnormal EGFR signaling in cancer cell with this EGFR-C797S mutation. The urgentunmet clinical demand is to develop new therapeutics to overcome EGFR-TKI resistance mediated byEGFR-C797S mutation. In this proposal, we strategically use an addicted triple resistant mutant(L858R/T790/C797S) EGFR-expressed Ba/F3 cells to screen for potential novel compounds to overcomeEGFR-TKI resistance mediated by EGFR-C797S mutation in lung adenocarcinoma. There are four followingspecific aims: (1) To perform and validate the cell-based HTS assay for identifying specificEGFR-L858R/T790/C797S activity inhibitors by compound library screening. (2) To investigate thebinding sites between EGFR and these potential compounds. (3) To modify the functional structure ofthe candidate compounds and increase the specificity and efficacy of potential compounds. (4) Toexamine the benefits of these lead compounds in pre-clinical animal model. We hope the potential leadcompounds identified may overcome the EGFR third-generation TKI resistance and can eventually translateinto clinical application and prolong the survival of patients with lung adenocarcinoma.
Keyword(s)
表皮生長因子受體(EGFR)
突變
抗藥性
C797S 點突變
EGFR
HTS
C797S
EGFR-TKI
HTS