RET in breast cancer: pathogenic implications and mechanisms of drug resistance

Abstract

Initiation, progression, outcome and sensibility to therapies in breast cancer (BC), the most frequent cancer in women, are driven by somatic and germline mutations. Although the effectiveness of hormonal therapies is well-founded, it is prescribed for cancers which express steroid hormone receptors, such as estrogen receptor (ER). RET is a protooncogene encoding a transmembrane tyrosine kinase receptor that is activated by one of its four ligands (GDNF, neurturin, artemin or persephin) and one of its coreceptors (Gfrα1-4). Loss-of-function mutations in RET are responsible for Hirschsprung disease, while gain-of-function mutations for multiple endocrine neoplasia type 2. In addition, deregulation of its intracellular signaling, due to mutations, gene rearrangements, overexpression or transcriptional upregulation, can cause several neuroendocrine and epithelial tumors. In BC, amplification of receptor tyrosine kinases, such as ERBB2, EGFR, IGFR and FGFR1, and/or their upregulation contribute to cancer initiation and progression. RET can also have an important role in BC, but only in the subset of ER-positive (ER+) tumors, where it is found overexpressed. Targeting the RET pathway and shedding light on molecular basis of the resistance to hormone therapy may lead to new therapies in ER+ BC, improving treatment outcome and preventing tumor-related events. Thus, here, we review the state of the art of RET biology in BC and agents targeting RET tested in the clinical trials and discuss the specificity of the still available RET inhibitors and the molecular mechanisms underlying the BC resistance to endocrine therapy.

Efficacy and safety of pyrotinib combined with albumin‐bound paclitaxel as first‐line treatment for HER2‐positive metastatic breast cancer in patients previously treated with adjuvant and/or neoadjuvant trastuzumab therapy: The stage 1 results of a single‐arm, phase 2 prospective clinical trial

“… 54 In addition to its involvement in the initiation and progression of breast cancer, 55 studies found that RET was associated with resistance to endocrine therapy. 56 Our results are consistent with the effects of RET in promoting cancer cell proliferation and invasion, as patients with high RET expression demonstrated shorter PFS.…”

Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer

“…S4; ref. 28 ). As a comparison, the WHIM9 PDX line, which expresses WT ERα and showed partial sensitivity to E2 deprivation ( 7 ) has a relatively low level of RET (lower 50% percentile), but the expression of RET mRNA and protein was highly E2 induced (upper 25% percentile), as expected, given that RET is directly transcriptionally regulated by ERα ( Fig.…”

A comprehensive overview of the relationship between RET gene and tumor occurrence

“…RET amplification is the most common, followed by RET fusion. Most RET mutations in BC appear after drug resistance, and CCDC6-RET and NCOA4-RET occur frequently ( 50 ). RET is actionable in ER + BC.…”