Acetyltanshinone IIA is more potent than lapatinib in inhibiting cell growth and degrading HER2 protein in drug-resistant HER2-positive breast cancer cells
CANCER LETTERS
Authors: Huang, Bin; Yip, Wai Kien; Wei, Na; Luo, Kathy Qian
Abstract
High expression of human epidermal factor receptor 2 (HER2) is directly related to tumor progression, malignancy and drug resistance in HER2-positive breast cancer (HER2-PBC). The major limitation of current anti-HER2 therapies is that they cannot reduce the levels of HER2 protein. Here, we investigated the effect of acetyltanshinone IIA (ATA) in lapatinib-resistant HER2-PBC cells. Our data showed that ATA exhibited more potent effects than lapatinib against drug-resistant HER2-PBC cells in terms of (1) inhibiting cell growth, (2) reducing phosphorylated and total HER2 levels, (3) inhibiting tumor xenograft growth in nude mice, and (4) reducing HER2 protein levels in tumor xenografts. A mechanistic study revealed that ATA promoted HER2 degradation via increasing c-Cbl and CHIP-mediated HER2 ubiquitination and subsequent HER2 degradation by the proteasome or lysosome. ATA also reduced the levels of other tyrosine kinase receptors (TKRs), such as HER3, IGF-1R and MET, in lapatinib-resistant cells. Our findings suggest that direct degradation of HER2 and other TKRs can be an effective strategy for combatting drug resistance. They also indicate the potential utilization of ATA in treating breast cancer that is resistant or nonresponsive to current HER2-targeted therapies.
Place of anti-EGFR therapy in older patients with metastatic colorectal cancer in 2020
JOURNAL OF GERIATRIC ONCOLOGY
Authors: Gilabert, Marine; Ries, Pauline; Chanez, Brice; Triby, Simon; Francois, Eric; Lievre, Astrid; Rousseau, Frederique
Abstract
Almost half of the new cases of colorectal cancer concern patients aged >= 70 years. However, very few clinical trials have specifically included older patients. As a consequence, the treatment of these patients is controversial because the balance between clinical benefits and toxicities remains uncertain. In patients without comorbidities and with an ECOG performance score of 0-1, treatment indications are similar to those of younger patients. For frail patients, chemotherapy is possible, but a comprehensive geriatric assessment is recommended. Anti-EGFR (epidermal growth factor receptor) therapy is indicated either in combination with chemotherapy in the first-line or second-line setting or as monotherapy in the third-line setting (i.e., after failure of chemotherapy). For fit older patients, clinical trials that compared chemotherapy alone with doublet chemotherapy plus anti-EGFR in either first-line or second-line setting suggested that age is not an absolute contraindication for the use of this regimen. In frail patients, anti-EGFRmonotherapy in the first-line, second-line or third-line setting has shown feasibility and antitumor activity and had mainly cutaneous toxicities that were easily managed. In any case, administration of treatment must be very cautious in older patients and the treatment dose needs to be adapted according to comorbidities. (C) 2020 Elsevier Ltd. All rights reserved.
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