Br J Cancer: Comparative analysis of three tyrosine kinase inhibitors targeted at HER2

The ERBB2/HER2 (skin growth factor 2) gene is often amplified or mutated in cancer.
previous studies have confirmed gene amplification of HER2 and over-expression of proteins in breast and other cancers, and many her2-targeted therapies have been developed and approved.
the current her2-targeted therapies can be broadly divided into three categories: Herceptin (Curto Bead Monoantin, Herceptin) and Pato Pearl Monoanti (Perjeta); DM1, Kadcyla) drug-drug bindings with curto-bead monoanto-deuxtecan (Druticon, DS-8201, Enhertu);
of these, TKIs targeting HER2, lapatinib, Tykerb/Tyverb, neratinib, Nerlynx and Tucatinib, Tukysa, are currently FDA-approved for the treatment of HER2 plus positive breast cancer.
these drugs are oral and target the kinase domain of HER2.
of TKIs targeting HER2 is currently limited to small-scale studies of the direct comparison of TKI preclinical efficacy.
with the increase in the number of treatments available for the first-line treatment of the incurable HER2 plus breast cancer, there is an urgent need to understand and distinguish the relevant clinically recognized TKI factors.
identify beneficial patient populations by identifying new biological markers.
the study, the researchers used 115 cancer cell line to directly compare the anti-proliferation effects of the three TKI.
the new TKI reaction/resistance markers by cross-analyzing the drug response spectrum with mutations, gene copies, and expression data.
the results of the drug response to breast cancer cell line showed that all three TKI models were effective for HER2 amplification.
the strongest activity in the world, followed by tucatinib and finally lapatinib.
is most active in cells with HER2 mutations and EGFR mutations.
further studies have shown that high expressions of HER2, VTCN1, CDK12 and RAC1 are associated with three TKI reactions.
and the expression of genes associated with DNA damage repair is associated with TKI resistance.
BRCA2 mutations were associated with the reactions of lynatrini and takatinibs, while the high expressions of ATM, BRCA2 and BRCA1 were associated with the resistance of lynatinibs.
, the results show that lynatinib is the most effective TKI treatment for HER2 amplification, mutation and EGFR mutant cell lineage.
the study also provides potential drug resistance mechanisms for the development of combination therapies targeting HER2.