Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
Metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutations responds very well to first and second generation tyrosine-kinase inhibitors (TKI) including gefitinib, erlotinib and afatinib. Unfortunately, drug resistance will eventually develop and about half of the cases are secondary to the emergence of acquired T790M somatic mutation. In this work, we prospectively recruited 68 patients with metastatic EGFR-mutated NSCLC who have developed progressive disease after first-line TKI with or without subsequent TKI and/or other systemic therapy. Liquid biopsy after progression to their last line of systemic therapy were taken for detection of acquired T790M mutation. By performing attribute ranking we found that several attributes, including the initial EGFR mutational type, had a high correlation with the presence of acquired T790M mutation. We also conducted computational studies and discovered that the EGFR mutation delE746_A750 had a lower stability around the residue T790 than delS752_I759 and L858R, which was consistent with our clinical observation that patients with delE746_A750 were more likely to acquire T790M mutation than those with delS752_I759 or L858R. Our results provided new insight to future direction of research on investigating the mechanisms of acquired T790M mutation, which is essential to the development of novel mutation-specific TKIs.
|Gefitinib||17/28 (60.7%)||0/3||7/23 (30.4%)||24/54 (44.4%)|
|Erlotinib||4/9 (44.4%)||0/1||0/5 (0%)||4/15 (26.7%)|
|Afatinib||4/6 (66.7%)||0/0||1/5 (20.0%)||5/11 (45.5%)|
|Overall||19/31 (61.3%)||0/3||8/31 (25.8%)||27/65 (41.5%)|
Table 1. Probability of acquiring T790M for different initial EGFR mutations and different tyrosine-kinase inhibitors. We found that 61.3% of patients with the delE746_A750 mutation acquired T790M, compared to no patients and 25.8% of patients with exon 19 non-LRE deletions and L858R mutation respectively (p = 0.0059).
Figure 1. The cumulative average stability for (A) EGFR mutant-afatinib complexes, (B) EGFR mutant-erlotinib complexes, (C) EGFR mutant-gefitinib complexes and (D) EGFR mutants without ligand. The cumulative average stability for residue index k corresponded to the average stability of the first k residues closest to the residue T790. We found that for all three TKIs, delE746_A750 had a higher value (i.e. lower stability) around T790 than the other two mutations, delS752_I759 and L858R. This result was consistent with the fact that patients with delE746_A750 were more likely to acquire a second T790M mutation than patients with delS752_I759 or L858R after taking gefitinib, erlotinib or afatinib as 1st line therapy. We also carried out simulations for EGFR mutants without ligand. We found that in this case, the stability results also roughly the same as those discussed above.[Back]