Mechanisms of Acquired Resistance to AZD9291

Abstract

Acquired resistance mechanisms of AZD9291 in patients with EGFR-mutant NSCLC who failed treatment with first-generation EGFR TKIs include the loss of EGFR-mutant clones plus alternative pathway activation or histologic transformation and EGFR ligand-dependent activation.

Third generation EGFR TKIs: current data and future directions

“…In vitro analysis demonstrated that FGF2 supplement conferred resistance to osimertinib in EGFR-mutant NSCLC cells [72]. Clinically FGFR amplification after progression on osimertinib were reported after osimertinib [72].…”

“…Clinically FGFR amplification after progression on osimertinib were reported after osimertinib [72]. …”

“…Small cell lung cancer (SCLC) transformation- a known rare mechanism of resistance to first generation TKI, has been described after treatment with third generation TKIs [54, 72–74]. These transformed SCLCs can continue to harbor their original EGFR-activating mutations, but not T790 M [54, 72–74].…”

“…These transformed SCLCs can continue to harbor their original EGFR-activating mutations, but not T790 M [54, 72–74]. Genome sequencing revealed RB1 mutation and loss of RB1 in these SCLC after acquired resistance to 3rd generation TKI, suggesting that these mutations play critical roles in driving the transformation [54, 72]. Co-occurring P53, PTEN and PIK3CA mutations have also been reported in a patient with small cell transformation after osimertinib [74].…”

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

“…It is the resistance mechanism of EGFR most commonly known. This acquired resistance is mediated by a threonine-to-methionine mutation in EGFR at position 790 (EGFR T790M), activation of a bypass-signalling pathway such as mesenchymal-epithelial transition (MET) pathway, human epidermal growth factor 2 (HER2), or mitogen-activated protein kinase 1 (MAPK1) amplification, and histologic transformation to small-cell lung cancer or an epithelial-to-mesenchymal transition [12][13][14][15]. Following the acquisition of the mutation, the median survival is less than two years, so there is a need to develop new drugs that will control tumor growth in patients positive EGFR T790M.…”