THE BLOCKAGE OF THE IL6-STAT3 PATHWAY CAN RESTORE TRASTUZUMAB SENSITIVITY IN HUMAN PDX RESISTANCE TUMORS.

REAL SEBASTIAN; MARIA ROQUE MORENO

Mar del plata

Congreso; Reunión anual de sociedad Argentina en Investigación clínica.; 2022

Introduction: In breast cancer (BC), resistance to the Mob Trastuzumab(TZM) is the main cause of dead in HER2+ patients and occurs in around 30% of primary and up to 70% of metastatic tumors. Several pathways are involved in this resistance, and new drugs against them are used as second and thirst line of treatment. Previous in vitro studies have suggested that the IL6-STAT3 pathway, (an independent HER2 pathway) could be involved in TZM resistance, probably 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 IL6R restores the TZM sensitivity in resistance human 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 IHQ. 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 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 resistance tumor (p=0,009), suggesting a basal effect of the drug. The combination of TZM and Tocili generated a stronger reduction in the kinetic of growth when is compared with TZM alone, similar to the sensible parental tumor (p=0,004).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 of TZM resistant patient. Actually we are expanding the analysis to others humans PDX BC tumors.