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CB2R loss drives trastuzumab resistance by reorganizing HER2 dimers to evade IFN-γ and enhance EGFR signaling

ABSTRACT: Despite advances in HER2+ breast cancer treatment, resistance to anti-HER2 therapies remains a significant clinical challenge. This study investigated the role of the endocannabinoid system, specifically the HER2-CB2R heterodimer, in trastuzumab resistance mechanisms. Analysis of human breast cancer samples revealed that decreased HER2-CB2R expression following neoadjuvant treatment, primarily due to CB2R reduction, correlated with poor long-term outcomes. Using cell and animal models, we demonstrated that trastuzumab resistance is dependent on CB2R expression, as it occurs upon CB2R downregulation and is reversible through CB2R re-expression. Mechanistically, CB2R loss enables cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB2R to HER2-EGFR dimers, reducing dependence on HER2 signaling and increasing reliance on EGFR-mediated pathways. Importantly, EGFR inhibition resensitized resistant cells to trastuzumab's antitumor effects. This work identifies a novel resistance mechanism involving CB2R-mediated receptor heterodimerization and IFN-γ signaling modulation, establishes HER2-CB2R/EGFR heterodimer status and CB2R/EGFR expression as potential predictive biomarkers, and supports dual HER2/EGFR targeting as a promising strategy to overcome trastuzumab resistance in HER2+ breast cancer patients.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Ana Montero Calle

LAB HEAD: Rodrigo Barderas

PROVIDER: PXD065700 | Pride | 2026-05-07

REPOSITORIES: Pride

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Project description:HER2 targeting with trastuzumab has changed the prognosis of breast cancer patients carrying amplification and/or overexpression of this oncogene. Despite this progress, however, resistance to trastuzumab occurs in the vast majority of patients. Newer anti-HER2 therapies, like the dual tyrosine-kinase inhibitor (TKI) lapatinib, show antitumor activity in a limited proportion of patients, indicating that HER2 can be still exploited as a target after trastuzumab failure. However, due to the high proportion of patients that fail to respond to these alternative strategies, it is reasonable to assume that cells escaping HER2 targeting may rely on alternative pathways not involving HER2 to sustain their growth. Their knowledge is relevant for exploiting new therapies. To investigate this hypothesis we generated a human HER2 overexpressing breast cancer cell line resistant to trastuzumab and lapatinib (T100) and we have characterized it genetically and molecularly. In T100 cells, the previously proposed mechanisms of resistance to HER2 inhibitors did not explain cell escape. Notably, silencing HER2 by shRNA did not affect the growth of T100 cells, suggesting loss of reliance upon HER2. Among the alternative pathways that we explored, altered levels of the antiapoptoptic proteins Mcl-1 and Survivin were observed. This suggested the possibility of targeting resistant cells with the multitarget inhibitor sorafenib. Moreover, sorafenib, nearly inactive in parental cells, strongly inhibited the in vitro growth of T100 cells. In conclusion, we provide a new model where the activation of HER2 independent mechanisms sustains the growth of tumor cells, significantly increasing the sensitivity to sorafenib. Keywords: HER2, breast cancer, resistance, trastuzumab, lapatinib, sorafenib Total RNA was isolated using TRIZOL reagent (Life Technologies, Gathersburg, MD) and quantified by Bioanalyzer 2100 (Agilent Technologies); following the isolation procedure, mRNA was amplified starting from 1μg using MessageAmp II aRNA Amplification kit (Ambion Inc. Austin TX, USA). Ammino-allyl modified nucleotides were incorporated in in vitro transcription step according to the manufacturer’s protocol. Labeling was performed using NHS (N-hydroxysuccinimidyl) ester Cy3 or Cy5 dies (GE Healthcare Europe GMBH, Upsala - Sweden) able to react with the modified RNA. At least 5 μg of mRNA, for each sample, were labeled and purified with columns respectively. The Dye-Swap replication procedure was applied, in order to increase the accuracy of results. Samples were hybridized on 44K glass arrays (Agilent Technologies). Arrays were scanned and the images obtained were analyzed by the Feature Extraction software Agilent (version 9.5) and the text files were then processed using the Bioconductor package Limma (Linear models for microarray analysis).

			Action	DRS
	CB2R.mgf	Mgf
	CB2R.msf	Msf
	CB2R.mzML	Mzml
	CB2R.raw	Raw
	HER2.mgf	Mgf

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CB2R loss drives trastuzumab resistance by reorganizing HER2 dimers to evade IFN-γ and enhance EGFR signaling

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