In-depth analysis of osimertinib resistance mechanism

*For medical professionals to read only for reference.
To solve the problem of EGFR-TKI resistance, we must first clarify the mechanism of resistance.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can improve EGFR-mutant advanced non-small cell lung cancer (NSCLC) The overall survival of the patient
.

Osimertinib is an irreversible third-generation EGFR-TKI.
It is highly selective for EGFR sensitive mutations and EGFR T790M mutations.
It has demonstrated its high efficiency and low toxicity in the AURA series and FLAURA studies
.

Due to the high degree of tumor heterogeneity of NSCLC and the adaptive changes of cell signaling pathways, the acquired resistance of osimertinib can be roughly divided into: EGFR-dependent resistance and non-EGFR-dependent resistance mechanisms [1]
.

EGFR-dependent drug resistance EGFR-dependent drug resistance mechanisms include: EGFR mutations that still retain the T790m mutation.
In a clinical study on AURA3 [2], 21% of patients had acquired EGFR mutations (the incidence of c797s was about 14 %); 49% of patients in AURA3 had T790M mutation loss during disease progression.
Among these patients with T790M mutation loss, patients with ex19del at baseline were more likely to have a loss of T790M mutation than patients with L858R insertion (83% and 14%, respectively)
.

The most common tertiary EGFR mutation is EGFR C797S.
In addition, many rare site mutations in EGFR have been found [1]: For example, mutations in residues G796 (G796R, G796S and G796D) adjacent to C797 may be in space.
Structurally interfere with the effect of osimertinib-EGFR; EGFR gene L792, the frequency is 10.
8%, L792 almost always presents a cis configuration with T790M, the mutation itself can lead to drug resistance; EGFR gene L718/G719, the frequency is 9.
7%, L718 is located at the ATP binding site of the EGFR protein kinase domain, which itself can lead to drug resistance; the G724S mutation in the P loop of the EGFR kinase domain induces conformational changes in the receptor, thereby affecting the binding of osimertinib; 20 Exon mutations (such as s768I, 20ins, etc.
); In addition, it has recently been discovered that EGFR wild-type allele amplification is also one of the important causes of drug resistance
.

EGFR-independent drug resistance EGFR-independent mutations [1] include: MET amplification (19%), cell cycle gene changes (12%), HER2 amplification (5%), PIK3CA (5%), RASMAPK pathway activation , Oncogene fusion (4%), BRAF V600E (3%), gene phenotype transfer and many other complex mechanisms
.

References: [1].
Alessandro Leonetti, Sugandhi Sharma, et al.
Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer.
[2].
Papadimitrakopoulou VA, Wu Y.
-L.
, Han J.
-Y .
, Ahn M.
-J.
,Ramalingam SS, John T.
et al.
LBA51 Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study.
Ann.
Oncol.
29, https:// doi.
org /10.
1093/annonc/mdy424.
064 (2018).
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