Non-small-cell lung cancer: how to manage RET-positive disease

Abstract

Targeted therapy has dramatically changed the history and outcomes of oncogene-addicted non-small-cell lung cancer (NSCLC). RET rearrangements are typically observed in about 1-2% of NSCLC, resulting in constitutive activation of downstream signalling pathways commonly involved in cell growth and survival. RET-positive NSCLCs are generally associated with young age, non-smoking history, a high rate of brain metastases at diagnosis and an immunologically 'cold' tumour microenvironment. Multi-kinase inhibitors, such as cabozantinib, lenvatinib and vandetanib, showed limited efficacy but significant toxicity mainly linked to offtarget effects. In contrast, two RET-selective tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, demonstrated high response rates and manageable safety profiles, and have received FDA approval for the treatment of advanced RET-positive NSCLC regardless of previous lines of treatment. Despite the initial high response rate to RET-TKIs, most patients inevitably develop disease progression due to acquired resistance mechanisms by both on-target or off-target mechanisms. To date, new potent and selective next-generation RET-TKIs are currently being evaluated in ongoing clinical trials in order to overcome resistance and improve efficacy and blood-brain barrier crossing. Genomic recharacterization at progression could help guide treatment choice or enrolment in clinical trials of specific next-generation RET inhibitors. Here, we review the biology, clinicopathological characteristics, targeted therapies and mechanisms of resistance of advanced NSCLC harbouring RET fusions to provide treatment guidance for these patients.

Small bowel edema and lymphocytic duodenitis as severe reversible gastrointestinal toxicity of selpercatinib in RET fusion–positive non–small cell lung cancer: a case report

“…These pathways include RAS – MAPK , PI3K – AKT , PKC , and JAK – STAT . RET rearrangements are caused by the fusion between the C-terminal region of RET and the N-terminal region of other genes as KIF5B , CCDC6 , and NCOA4 , resulting in a chimeric fusion protein constitutively active, with consequent aberrant downstream signaling of cell proliferation ( 12 ). Because of its interaction with the GDNF , RET has an important role in the development and function of the enteric nervous and renal system ( 13 ).…”

Construction of a multiple-class classifier based on mRNAs and lncRNA FAM66A and PSORS1C3 for predicting distant metastasis in lung adenocarcinoma

“…Cancer deaths around the world are mainly from nonsmall cell lung cancer (NSCLC), and histopathological assessment is involved in its diagnosis (32,33). Experienced pathologists mainly evaluate the stage, type, and subtype of lung cancer by visual inspection of histopathological slides (34,35) Similarly, a recent study found that increased CYP4F12 expression in hepatocellular carcinoma is inversely connected with decreased expression of cell cycle-associated genes (40).…”

Targeted therapeutic options in early and metastatic NSCLC-overview

“…Histologically, they are almost exclusively of the adenocarcinoma subtype; others showed 92.3% non-squamous histology [ 89 ]. Several fusion partners of RET are known, the most common being KIF5B and CCD6C [ 90 ]. IHC and RT-PCR have proven to be unreliable methods for diagnosing RET-positive NSCLCs due to their low sensitivity and variable specificity and are replaced by FISH and NGS [ 85 , 90 ].…”

“…Several fusion partners of RET are known, the most common being KIF5B and CCD6C [90]. IHC and RT-PCR have proven to be unreliable methods for diagnosing RET-positive NSCLCs due to their low sensitivity and variable specificity and are replaced by FISH and NGS [85,90].…”