Scientists at the University of Turku Bioscience Center in Finland have recently identified that a protein trafficking receptor studied mainly in neurons, plays an essential role in breast cancer metastasis. The research team observed that the Sortilin-related receptor (SorLA) functionally contributes to the most reported therapy-resistant mechanism by which the cell-surface receptor HER3 counteracts HER2 targeting therapy in HER2-positive cancers. Moreover, the Finnish researchers showed that removing SorLA from cancer cells sensitized anti-HER2 resistant breast cancer brain metastasis to targeted therapy. Findings from the new study were published recently in Oncogene through an article titled, “A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance.”

HER2 protein is a strong driver of tumor growth. HER2 amplification occurs in about 20% of breast cancers and overexpression or amplification of HER2 is also commonly found in bladder and gastric cancers. HER2 targeting therapies, such as Herceptin, are widely used in clinical care and it plays an important role in the treatment of HER2-positive cancers.

“HER2 tumors can become therapy resistant by upregulating HER3. Currently, these tumors are un-druggable as there are no HER3 targeted therapies available,” explained lead study investigator Hussein Al-Akhrass, PhD, a postdoctoral researcher at the University of Turku. “Our study showed that removing SorLA protein from drug-resistant HER2-positive cancer cell lines sensitized breast cancer brain metastasis to anti-HER2 therapy. To date, very little has been known about SorLA in cancer. Our discovery that HER3 receptor-induced drug resistance is dependent on SorLA was surprising since this cancer type and its resistance mechanisms have already been widely studied.”

However, some patients will eventually progress during the Herceptin treatment and therapy resistance is frequently linked to the upregulation of the HER3 receptor. The newly discovered role of SorLA in supporting HER3 expression and drug resistance offers novel possibilities to target drug-resistant HER2 positive cancers in the future.

“Understanding the response to HER2-HER3 signaling and the regulation of the dimer is essential to decipher therapy relapse mechanisms,” the authors wrote. “Here, we investigate a bidirectional relationship between HER2-HER3 signaling and a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA; SORL1). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner.”

A new understanding of these mechanisms enabled the possibility to control the growth of breast cancer cells in their most aggressive situation when they form tumors in the brain. In vitro cell culture experiments showed that SORLA protein promotes the recycling of HER3 receptors back to the plasma membrane, where the receptor is active and drives the proliferation of cancer cells. When SorLA was removed, the HER3 receptor was destroyed in cells leading to sensitization of the cells to anti-HER2 therapy.

The next goal for the research group is to find a way to block the function of SORLA in tumor cells and therefore if there could be a way to develop SORLA targeting treatment.

“This [study] highlights SorLA as a potential target for the development of combination therapies aimed at overcoming HER3-mediated resistance of HER2-positive breast cancer patients to existing anti-HER2 therapies,” the authors concluded.

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