Lapatinib resistance mechanism

Lapatinib, a dual kinase inhibitor targetingHER2 and EGFR, has demonstrated significant antitumor activity against HER2-positive breast cancer cells, including those that are resistant to trastuzumab. Its mechanism of action is unique. Unlike trastuzumab, lapatinib can induce apoptosis in HER2-positive breast cancer cells in vitro, while trastuzumab has no such effect. This discovery provides a new perspective on the treatment of HER2-positive breast cancer.

However, despite the clinical efficacy of lapatinib in the treatment of trastuzumab-resistantHER2-positive breast cancer, a significant proportion of patients will still experience disease progression due to acquired resistance to the drug. This prompted researchers to delve into the mechanism of lapatinib resistance. Preclinical studies have shown that changes in proteins that regulate intrinsic and extrinsic apoptosis pathways are closely related to lapatinib resistance, among which members of the inhibitor of apoptosis protein (IAP) family, members of the B-cell CLL/lymphoma 2 (BCL-2) family, and the TNF-related apoptosis-inducing ligand (TRAIL) receptor all play important roles.

To gain a deeper understanding of lapatinib resistance, this research team examined two acquired lapatinib-resistant cell line models (SKBR3-L and HCC1954-L). The study found that lapatinib was unable to induce apoptosis in these two drug-resistant cell lines. Further analysis revealed that changes in BCL-2 protein family members, especially MCL-1 and BAX, may play a key role in lapatinib resistance.

In response to this finding, the research team tested obatoclax, a therapeutic inhibitor targetingMCL-1. The results showed that both SKBR3-L and HCC1954-L cells were more sensitive to obatoclax-induced apoptosis than their parental cells. In addition, the study unexpectedly found that the development of acquired resistance to lapatinib resulted in acquired sensitivity of SKBR3-L cells to TRAIL. This sensitivity is associated with decreased AKT phosphorylation, increased FOXO3a expression, and decreased c-FLIP expression. In SKBR3-L cells, TRAIL treatment can activate caspase 8, caspase 9 and caspase 3/7, thereby triggering apoptosis. However, in the second drug-resistant model HCC1954-L cells, the sensitivity of these cells to TRAIL was not enhanced because p-AKT levels were not reduced.

Notably, combining obatoclax with TRAIL improved the response of SKBR3-L cells but had no effect on HCC1954-L cells. This discovery not only reveals the heterogeneity that exists between different drug-resistant cell lines, but also provides new treatment strategies and potential biomarkers for HER2-positive breast cancer that is resistant to HER2-targeted therapy.

Taken together, this study highlights the possibility of overcoming acquired lapatinib resistance by altering apoptotic signaling and provides a new direction for the future treatment of HER2-positive breast cancer.

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Reference materials:https://pmc.ncbi.nlm.nih.gov/articles/PMC6180577/