TNFα induces multiresistance to HER2targeted TNFα induces multiresistance to HER2targeted therapies in HER2positive breast cancer

BRUNI S; AMASINO M; SCHILLACI R; DE MARTINO M; RIVAS MA; MERCOGLIANO MF; ELIZALDE PV; VENTURUTTI, L; PROIETTI C

Congreso; 108th Annual Meeting of the American Association for Cancer Research; 2017

AACR

HER2 positive (HER2+) is a breast cancer (BC) subtype characterized by HER2 overexpression/amplification that affects nearly 15% of BC patients andcorrelates with poor prognosis. These patients receive trastuzumab (T), an antiHER2monoclonal antibody, but resistance events (4060%)hamper its clinicalbenefit. Previously we have demonstrated that TNFα (TNF) induced mucin 4 (MUC4) expression and turned Tsensitivecell lines and tumors into resistantones.Nowadays, new antiHER2therapies are being used in the clinical setting, such as lapatinib (a dual inhibitor of EGFR and HER2), and antibodies like TDM1(combines TZ with the antimicrotubuleagentemtansine), and pertuzumab (P) that impeds HER2 dimerization.The aim of this work was to study the role of TNF in resistance to the new HER2targetedtherapies.We used BT474C(control cells) and BT474T2,engineered in our lab to stably overexpress TNF, and were proven to be sensitive and resistant to T,respectively.We performed doseresponsecurves for TDM1,they show that inhibits proliferation of BT474Ccells at 0.01 μg/ml. On the other hand, BT474T2cellswere resistant in the same experimental conditions and they exhibited reduced TDM1binding with respect to BT474C.BT474Ccells were sensitive to lowconcentrations of TDM1with 0.51 nmol/L, but in BT474T2cells TDM1was ~10 times less potent than control cells (IC 50 3.34 nmol/L). When weabrogated MUC4 expression, BT474T2cells were sensitized to TDM1,showing that TNFinducedMUC4 expression is responsible for TDM1resistance inthis cell line.We assessed the effect of lapatinib performing a doseresponsecurve. Results shown a similar IC50 for BT474C and T2 cells (0.26 μM and 0.28 μM,respectively).When we studied P effect, we observed that the combination of T+P was more effective inhibiting proliferation in BT474Ccells than T alone, despite theseresults binding of the antibody showed no change between the cell lines. In BT474T2cells proliferation was slightly inhibited by the combined treatment. Invivo experiments showed that BT474Ctumors were sensitive to T and the combination of T+P, but BT474T2tumors did not respond to any of thesetreatments.These results suggest that TNF plays an important role in multiresistance to HER2targetedtherapies, specifically TDM1and P, but not in lapatinib resistance.We propose TNF as an attractive target and we suggest that HER2+ patients resistant to T could be eligible for a combination of HER2targetedtherapies and aTNFblockingtreatment to overcome resistance