(本篇文章仍再逐步編輯中)
而現今所有的EGFR inhibitor都幾乎是使用在NSCLC的adenocarcinoma。本篇將對肺癌EGFR的標靶治療 (target therapy)來作討論，內容主要為EGFR inhibitor的簡介、其使用時機、治療效果、和常見的resistance mechanism。
關於EGFR的基本介紹
EGFR是個細胞表現的tyrosine kinase receptor。一般所謂的EGFR mutation是指EGFR的hyperactivation，使癌細胞漸漸幾乎都依賴EGFR下游的proliferation signaling pathway，使癌細胞能夠生存和大量增生。當癌細胞都幾乎依賴某一個oncogene (這邊指EGFR)來得以生存下來，這現象稱之為 "oncogene addiction." 顧名思義，當我們「戒斷」癌細胞對某oncogene的依賴後，癌細胞就失去維生機制而漸漸死去。而這也是為什麼許多市面上的target therapy會有效的主要原因。
- ligands of EGFR: EGF and TGFa --> autocrine loop
- EGFR-target therapy --> rationale: to disrupt the loop
先前研究發現在頭頸癌、卵巢癌、子宮頸癌、膀胱癌、食道癌、胃癌、腦癌、乳癌、子宮內膜癌、肺癌、大腸癌，都可能有EGFR mutation，並且通常此類病人預後較差。
因此針對EGFR的抑制而研發出兩個新藥 :
- Gefitinib (商品名: Iressa) ，由AstraZeneca研發，於2003年美國FDA核准
- Erlotinib (商品名: Tarceva)，由 OSI Pharmaceuticals, Genentech研發，於2004年FDA 核准
EGFR mutation是甚麼?
如下圖所示，大部分的EGFR的突變點是在tyrosine kinase domain上，也就是EGFR的active site。因此，這些突變一部分會使得EGFR有activating mutation，也就是增加EGFR的tyrosine kinase activity（蛋白質活性）。但這可分為ligand dependent 或independent。
臨床上會依據biopsy或surgical excision的腫瘤去做分子檢驗，再依據結果 (mutation type)來決定治療。而通常exon 19 deletion和exon 21 L858R是使用EGFRi的適應症，也就是說 : 有這兩個mutation site的肺腫瘤對藥物反應較佳。
ligand independent EGFR mutation
- T790M in exon 20 (50% of EGFR mutations)
- reduced ATP affinity --> increased sensitivity to erlotinib
- EGFR mutations more restricted to NSCLC
- most clinical trial responses were seen in about 10% of NSCLC patients
- mostly in East Asians, females, non-smokers
- but if responsive, showed lasting response
- among responders, 77% have EGFR mutations
- among refractory patients, 7% have EGFR mutations
- exon 19 deletion mutations respond better than exon 21 point mutations (eg. L858R)
- among responders, exon 20 insertion mutations never found
- but EGFR mutations correlations with TKI sensitivity is controversial
- 10-20% partial responders have no EGFR mutations
--> EGFR mutations not the sole determinant of TKI sensitivity/response
- in most cases, resistance occurs in 6-12 months
- clinical trial: overall survival improvement observed in erlotinib (BR21 trial), but not gefitinib (ISEL trial) --> withdrawal of gefitinib from US and European markets
--> approval of erlotinib as third-line therapy
** but there are differences between the two trials
- gefinitib (still in use in Asia) and erlotinib are comparable research/laboratory-wise
Primary Resistance
-tumors that have EGFR mutations may have additional genetic lesions to relieve this addiction, that may confer resistance --> may be those other lesions driving tumorigenesis, and not EGFR
- exon 20 mutations is 100-fold less sensitive to EGFR-TKIs
- almost all T790M have acquired resistance
- EGFR and KRAS mutations in NSCLC seems to be mutually exclusive
- 15-30% of NSCLC harbour KRAS mutation --> smoker-associated
- absence of KRAS mutation in EGFR-TKI responsive tumor
- in EGFR-TKI sensitive tumors, Akt activity decreased rapidly after therapy
- restoring PTEN mutation may regain erlotinib/gefitinib sensitivity (only in some cell types)
- other possible causes of primary resistance: PTEN, IGFR1, ERBB3, ERBB2
- but PTEN and IGFR1 are controversial
Acquired Resistance
- resistance generally develop in 6-12 months
- 50% of responders develop T790M mutations
- T790M may be only a subset of tumor cells, may exist before patient expose to drug --> may be further selected after drug exposure
- other mechanism: hyperactivation of downstream signaling that circumvent the receptor
- T790M weaken the interaction between inhibitor and kinase
(structurally similar to T315I in BCR-ABL, andT670I in c-KIT and T674I in PDGFRa)
參考文獻
