To examine mutational robustness, genotype was nested within disruption type and secondary mutation was nested under strain and disruption type.
As a result, the tumor also develops secondary mutation.
After drug treatment, the secondary mutation is subjected to selection and the cells with secondary mutation become a majority of the tumor.
Also, under the pressure of inhibitor, the tumor can develop secondary mutation because of its genetic instability.
The EGFRT790M secondary mutation has become a leading cause of clinically-acquired resistance to gefitinib and erlotinib.
Admittedly, it is hard to diagnose in each tumor whether the secondary mutation has already existed before drug treatment or not.
On the other hand, Asn655Thr mutation at exon 13 of the c-kit gene was observed as a secondary mutation in case 2 with secondary resistance to nilotinib.
One way is due to secondary mutation after crizonib treatment; and cells with third mutation dominate the tumor after being treated with second-generation ALK inhibitor.
Lorlatinib, an extremely selective ALK-TKI with activity also targeting ROS1 kinase, has been shown to overcome resistance mediated by the ALK G1202R secondary mutation in preclinical study.
A secondary mutation (T790M) in epidermal growth factor receptor (EGFR) is a hallmark of acquired resistance to EGFR inhibitors used to treat non-small-cell lung cancer (NSCLC).
For example, the secondary mutation T790M increases the affinity of EGFR for ATP and renders the EGFR kinase inhibitors gefitinib and erlotinib less effective in displacing this ATP (Yun et al., 2008).
