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Molecular changes of the transformation of NSCLC to SCLC TKI-resistant EGFR mutant cancers

 

Tyrosine kinase inhibitors (TKIs), such as gefitnib, erlotinib and afatinib, are effective clinical therapies for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, some patients develop secondary mutations in EGFR (T790M), amplification of the MET receptor tyrosine kinase, as well as mutations in PIK3CA. Those molecular changes activate key downstream signaling pathways of tyrosine kinase and confer resistance of TKI. A subset of resistant tumors transform to small-cell lung cancer via a serious of phenotypic and histological changes. Niederst et al. demonstrated the molecular changes occur in NSCLC to small-cell lung cancer (SCLC) transformed TKI-resistant EGFR mutant cancers. The article was published in Nature Communications.

 

Through analysis of tumor samples and cells lines derived from patients with SCLC transformed resistant cancers, researchers found transformed SCLC take on many features of classical SCLC, including the reduction or absence of EGFR expression, enhancement the effect of BCL-2 family inhibition, as well as the most remarkable feature: the lost of Retinoblastoma (RB). They observed a 100% lost of RB in all SCLC transformed tumors, but rarely in those that remain NSCLC. The findings reveal a subset of TKI-resistant cancers mimic many of the molecular and phenotypic characteristics of classical SCLC, lay a foundation of developing novel therapeutic strategies for TIK-resistant cancers.

 

Reference:
Nat Commun. 2015 Mar 11;6:6377.

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