EGFR独立的 AZD9291耐药机制

   研究发现 AZD9291耐药产生2类不同病例：her2和met扩增。有趣的是发生T790M突变的完全消失，在一个病例中，通过组织活检发现原发部位发生T790M突变而转移部位出现不同信号通路而产生耐药。建议联合her2或met抑制剂用药。

EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients.

Abstract

BACKGROUND:

AZD9291 is an oral, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI), which specifically targets both sensitizing and resistant T790M mutations. This compound has shown outstanding activity, in a phase I/II (AURA) trial. However, despite impressive tumor responses in T790M-positive patients, acquired resistance to this drug limits the benefit of this compound. Mutations at the EGFR C797 codon, located within the kinase-binding site, were very recently reported to be a potential mechanism of resistance to AZD9291 in T790M-positive patients.

PATIENTS AND METHODS:

To identify potential mechanisms of resistance to AZD9291, we report here on two patients with resistant biopsy specimens that had been treated with AZD9291.

RESULTS:

We identified in two distinct cases, HER2 and MET amplification by FISH and CGH as a potential mechanism of acquired resistance to third-generation EGFR-TKI. Interestingly, this event occurred with complete loss of the T790M mutation. In one case, we observed a different molecular status at two biopsy sites (the T790M mutation at the primary site and wild-type T790M at the metastatic site with different pathways of acquired resistance to AZD9291).

CONCLUSION:

Our observations suggest that T790M-positive and wild-type T790M clones may coexist at baseline. AZD9291 efficiently suppresses the growth of T790M-positive cells, but a population of wild-type T790M cells at baseline will mediate the development of resistance, here via a by-pass pathway activating either HER2 or MET.
http://www.ncbi.nlm.nih.gov/pubmed/26269204

前辈， 我理解这文章意识是野生790可以用过旁路激活，其实就是原发的790突变或许可以利用联合HER2和MET抑制剂来治疗

AZD9291耐药机制耐药后还可以有两种选择盲试吗？
联合her2或met抑制剂用药，这两种先后这么选择？联合还是9291吗？

不错的信息。

又看了下 意思应该是790突变可以用9291控制，耐药会造成野生型的790则通过HER2或MET等旁路通道形成转移，主要是说了耐药造成的790突变和野生的790突变可以共存，因为在原发部位检测到的是790突变，转移部位检测到的是野生790

T790是因为一代获得性耐药后产生的，那如果9291再次耐药，是不是说明T790靶点减少或消失，那一代靶点会不会有几率恢复可能呢？

学习了，谢谢分享

该文的意思是说，（第一代TKI耐药后）T790M阳性和野生T790M可以同时存在，9291可以完全抑制T790M阳性，但是野生T790M缺导致MET或者HER2突变，从而临床上表现为9291耐药。如果在9291抑制阳性T790M的同时，联合其它可以抑制MET和HER2的药，可以抵制或者延缓9291耐药。问题是，MET或者HER2的抑制剂就不会耐药吗？

9291耐药后的治疗，是需要好好去了解下了。