Deciphering the role of RET in cancer and breakthroughs in targeted treatments

Xueqing Hu , Ujjwol Khatri , Tao Shen , and Jie Wu, at University of Oklahoma Health Sciences Center, USA, provides a comprehensive review of the role of the RET (REarranged during Transfection) receptor tyrosine kinase in cancer development and the advancements in RET-targeted cancer therapies. RET, a transmembrane receptor tyrosine kinase, plays a crucial role in various cellular processes, including embryogenesis and cell development. However, when aberrantly activated due to mutations or chromosomal rearrangements, RET can act as an oncogenic driver in many cancers, notably non-small cell lung cancer (NSCLC).

The review discusses the early trials of multikinase tyrosine kinase inhibitors (TKIs) that were initially used to treat RET-altered thyroid cancer and NSCLC, with limited success. The development of more potent and selective RET TKIs, such as pralsetinib and selpercatinib, marked a significant advancement in RET-targeted therapy. These drugs have shown higher response rates and durability in treating RET-altered NSCLC and thyroid cancer, leading to their approval for advanced and metastatic RET-altered NSCLC and thyroid cancer in 2020. The FDA has also approved selpercatinib as a tumor-agnostic inhibitor for RET fusion-solid tumors, with pralsetinib expected to receive a similar approval.

Despite these advancements, challenges remain. Many patients exhibit incomplete responses to pralsetinib or selpercatinib, and drug-tolerant residual tumors can evolve resistance, leading to disease progression. The review summarizes the current knowledge and gaps in oncogenic RET alterations and RET-targeted cancer therapy, emphasizing the need to address resistance mechanisms and the future direction toward a cure.

Oncogenic RET alterations occur through genetic mechanisms like single nucleotide variants (SNVs), short insertions/deletions (indels), and gene fusions due to chromosomal rearrangements. The review delves into the specifics of RET mutations associated with multiple endocrine neoplasia type 2 (MEN2) and the aggressive nature of RET mutations in the cytoplasmic region, which are linked to MEN2B.

The article also highlights the various methods used to detect RET alterations, such as immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), DNA-polymerase chain reaction (DNA-PCR), reverse transcription-PCR (RT-PCR and RT-qPCR), and next-gen sequencing (NGS) of DNA and RNA. The advantages and disadvantages of these technologies are compared, with a focus on their usage in clinical research and practice.

Pralsetinib and selpercatinib are described as first-in-class, selective RET TKIs that have demonstrated high potency and selectivity for RET kinase inhibition, with less potency against other protein tyrosine kinases. The drugs have shown similar potency against both wild-type and gatekeeper mutated RET, unlike multikinase RET inhibitors, which are ineffective against gatekeeper mutants.

The review presents data from clinical trials of selpercatinib and pralsetinib, showing their efficacy in terms of objective response rate (ORR) and duration of response (DOR) in various RET-altered cancers. The most common adverse events associated with these drugs are also detailed.

Resistance to these drugs is discussed, with a focus on the mechanisms contributing to acquired TKI resistance, such as secondary target mutations and the acquisition of alternative driver oncogenes. The article underscores the importance of identifying and addressing these resistance mechanisms to improve treatment outcomes.

Finally, the review outlines the next generation of RET-selective kinase inhibitors that are in development to overcome resistance to current therapies. These new inhibitors are designed to target both solvent-front and gatekeeper mutations, offering hope for more effective treatments in the future.

In conclusion, the article emphasizes the significant progress made in understanding RET alterations and developing targeted therapies, while also acknowledging the challenges that lie ahead in managing resistance and improving patient outcomes in RET-driven cancers.