Science and Technology Production
Congress
Authorship
Real, Sebastian
;
ROQUE MORENO, MARIA
Date
2022
Publishing House and Editing Place
Fundación Revista Medicina (Buenos Aires)
Summary
Information provided by the agent in
SIGEVA
Introduction: Resistance to the Mob Trastuzumab (TZM) is the main cause of dead in HER2+ breast cancer patients and it occurs in around 30% of primary and up to 70% of metastatic tumors. Several pathways are involved in this resistance, and new drugs are used as second and thirst line of treatment. Previous in vitro studies have suggested that the IL6-STAT3 pathway could be involved in TZM resistance, probably by altering the stem cell proportion in the tumor. In the present work we demonstrate...
Introduction: Resistance to the Mob Trastuzumab (TZM) is the main cause of dead in HER2+ breast cancer patients and it occurs in around 30% of primary and up to 70% of metastatic tumors. Several pathways are involved in this resistance, and new drugs are used as second and thirst line of treatment. Previous in vitro studies have suggested that the IL6-STAT3 pathway could be involved in TZM resistance, probably by altering the stem cell proportion in the tumor. In the present work we demonstrate in a HER2+ PDX model generated in our lab, that the inhibition of IL6 receptor (IL6R) restores the TZM response in resistant tumors.M&M: A human HER2+ breast tumor was implanted in an immunosuppressed mice, and then transplanted to generate a HER2+ PDX line. ER, PR and KI67 status was confirmed by IHC. PDX mice were afterwards treated with increasing doses of TZM to obtain a resistant tumor. Mob Tocilizumab was used to inhibit IL6R. Results: The TZM resistant tumors were able to grow and resist almost doubled doses of TZM (p=0,045). To evaluate the effect of the blockage of the IL6-STAT3 pathway, we applied Tocilizumab (Tocili) that is used in clinic to treat advanced Covid19 patients and rheumatoid disease. The use of Tocili alone generated a small reduction in the tumor growth of TZM resistant tumor (p=0,009), suggesting a basal effect of the drug. And the combination of Tocili + TZM generated a stronger reduction in the kinetic of growth when compared to TZM alone (p=0,004), similar to the non-resistant tumor.Conclusion and perspectives: the blockage of IL6-STAT3 pathway can restore the sensitivity to TZM in a human HER2+ resistant tumor, suggesting the possible repurposition of Tocilizumab as a treatment for TZM resistant patient. Actually, we are expanding the analysis to more HER2+ PDX tumors.
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Key Words
RESISTANCETRASTUZUMABHER2IL6