HER2+ Breast Cancer Breakthrough: Can a New Combo Overcome Treatment Resistance?
"A Phase I study reveals how adding dasatinib to trastuzumab and paclitaxel shows promise in fighting HER2-overexpressing breast cancer by targeting resistance mechanisms."
Personalized medicine is revolutionizing cancer treatment by targeting specific vulnerabilities in tumors. A prime example is the development of anti-HER2 therapies, which have significantly improved outcomes for patients with HER2-overexpressing breast cancers. Trastuzumab, a monoclonal antibody, has become a cornerstone of treatment, but resistance remains a major challenge.
While trastuzumab offers undeniable benefits, most patients with HER2-positive metastatic tumors eventually experience disease progression. This has spurred the development of novel agents like lapatinib, pertuzumab, and T-DM1. However, understanding and overcoming resistance mechanisms is crucial to further improve outcomes.
Researchers have identified several mechanisms that contribute to trastuzumab resistance, including the activation of alternative signaling pathways and intrinsic changes in the HER2 receptor itself. Among these, the activation of the cytosolic kinase SRC has emerged as a key player. A new study explores whether combining dasatinib, an SRC kinase inhibitor, with trastuzumab and paclitaxel can improve outcomes in patients with HER2-overexpressing breast cancer.
Dasatinib: A New Weapon Against Trastuzumab Resistance?
Preclinical studies suggest that SRC inhibition can enhance trastuzumab activity. SRC was found to be activated in trastuzumab-resistant cells and breast cancer patients who progressed on the drug. By performing a tyrosine phosphoproteome analysis, researchers identified SRC as a mediator of resistance. In preclinical models, combining dasatinib with trastuzumab synergistically increased the antibody's activity, leading to DNA damage, cell cycle arrest, and apoptosis.
- Study Design: A "3+3" dose-escalation design was used, starting with two oral dose levels of dasatinib: 100mg (DL1) and 140 mg (DL2).
- Patient Population: Ten patients with HER2-overexpressing advanced breast cancer were enrolled.
- Recommended Dose: Dasatinib 100 mg daily was established as the recommended RP2D.
- Treatment Duration: The median number of administered cycles was 12 (range, 1 to 18).
Hope for Overcoming Resistance
This Phase I study demonstrates the feasibility of combining dasatinib with trastuzumab and paclitaxel, showing a manageable toxicity profile. This is especially important because the addition of dasatinib did not appear to significantly increase toxicities compared to the standard regimen.
The observed reduction in p-SRC expression confirms the drug's mechanism of action and supports the potential for this combination to overcome trastuzumab resistance. These findings align with preclinical models, suggesting that dasatinib enhances trastuzumab's activity by inhibiting the pAKT and pSRC pathways.
The ongoing Phase II study will further evaluate the efficacy of this combination in patients with HER2-positive breast cancer. If successful, this approach could provide a valuable new treatment option for patients who develop resistance to existing therapies, improving outcomes and quality of life.