In this study, we used the extensively molecularly characterized human NSCLC NCI-H1975 cell line which harbors two common EGFR point mutations, T790M and L858R, in exons 20 and 21, respectively, which is very sensitive to osimertinib, and its isogenic derivative osimertinib-resistant clone as a model system, to first develop a relevant humanized mouse model that models osimertinib acquired resistance accurately, and second, decipher cellular and molecular mechanisms for its acquired resistance. Here, EGFR is linked to non-small cell lung carcinoma.