“4HER” PROJECT: HER ONCOGENES FAMILY INTERACTION IN TRASTUZUMAB RESISTANT BREAST TUMORS.

EUGENIA COSTARELLI; REBECA RIOS; PABLO MANDÓ; MARÍA ROQUÉ; SEBASTIÁN REAL

Congreso; Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2022

INTRODUCTION: In breast cancer (BC), resistance to Trastuzumab (TZM) is the main cause of death in HER2 patients, occurring in 30% of primary and up to 70% of metastatic tumors. We propose that this happens, at least in part, due to the synergic functioning of HER2 with the other 4 members of the oncogene family. These receptors can compensate the inhibition of one of them by forming heterodimers among themselves, and generating resistance. We’ve previously developed a tool based on MLPA to determine the CNV of the 4oncogenes. Our analyses indicate that 15-30% of HER2 tumors present co-amplification with another family members. Our actual goal is to explore in vivo (patients) and in silico the association of co-amplified HERs with TZM response. OBJECTIVES: 1-Clinical study: To analyze in 50 HER2 breast tumors the correlation between the TZM response and CNV of the 4 HER oncogenes. 2- In silico study: To analyze in HER2 tumors from TCGA the clinical response variables associated with co-amplification of HER members, and identify the genes associated with a worst outcome.METHDOS: Clinical study: 50 HER2 patients treated in CEMIC (CABA) were included (9 neoadjuvant and 41 adjuvant), and DNA was extracted from FFPE tissue. MLPA assay was performed with the developed X026 probemix for HER oncogenes (MCR Holland). Pathologic complete response and recurrence was registered. In silico study: XENA/TCGA database was used to select the 67 HER2 patients (PAM50RNAseq phenotypic variable) from whom RNAseq data was obtained.RESULTS: Clinical study: To the date, we have analyzed by MLPA 27/50 tumors, and 24 were confirmed as HER2 (1 was discarded and 2 were HER2- by MLPA). ). We found that 9/24 samples (37%) presented co-amplification of HER2 with at least another HER oncogene (7/24 with 1 and 2/24 with 3 or more). So far, we have collected the clinical data of 19/50 patients, of which 3 (15,7%) presented disease recurrence. By MLPA we could determine that 1 was HER2- (and presumed to be refractory to TZM treatment), whereas the other 2 were HER2+ with HER3 co-amplification. In silico study: TCGA data revealed that BC patients presenting high co-expression of HER2/HER3 have the worst overall survival (OS) among all HER combinations. In a differential gene expression analysis, we found 57 upregulated and 71 downregulated genes in high HER/HER3 expressing tumors. By filtering genes with the strongest correlation (r>0,48) and worst OS, we identified 4 upregulated genes related to treatment resistance, and among 10 downregulated genes associated with immune infiltration.CONCLUSION: Our results suggest that the co-amplifications of HER family members can affect the outcome of HER2 BC patients, by affecting the regulation of other genes involved in resistance. Further studies are required to better understand how these oncogenes “work together for the family”.