Mutations in the KIT proto-oncogene and dysregulated platelet-derived growth factor receptor (PDGFR) signalling are well-established oncogenic drivers that are found in almost 85% of all gastrointestinal stromal tumors (GIST). These sarcomas, although rare, are notoriously resistant to chemotherapy which has led to the subsequent development of targeted therapies aimed at more successfully thwarting this disease.
Over recent years, much progress has been made in more effectively treating GIST thanks to the advent of a new generation of more potent and ‘smarter’ KIT and PDGFRA inhibitors. As an illustrative example, imatinib, a tyrosine kinase inhibitor that targets KIT, has shown clinical benefit in around 80-85% of patients with advanced GIST who receive treatment with this therapy. However, these patients will unfortunately and inevitably develop secondary resistance.
The specific molecular events that ultimately lead to the adaptive resistance of GIST to the current array of agents that hone in on KIT/PDGFRA mutations remain elusive and represent a major challenge in improving outcomes for these patients.
Now, results from a study led by César Serrano, Principal Investigator of VHIO’s Sarcoma Translational Research Group, have advanced precious insights into the possible causes of resistance by unmasking the E3 ubiquitin ligase Atrogin-1 (FBXO32) protein as a mediator of resistance to KIT-targeted inhibition in GIST.
Breaking potential new ground
Recently published as an Article in Oncogene*, the study investigators, including researchers from other VHIO groups and colleagues from various leading research centers in Spain, Germany, and the USA, assessed clinically representative in vitro and in vivo GIST models and GIST patients’ samples.
By next-generation sequencing (NGS) and using GIST-specific gene panels, the investigators studied multiple genes and associated pathways in KIT GIST, and discovered that that FBXO32, or Atrogin-1, is one of the most critical genes differentially expressed in GIST upon inhibition of KIT and KIT-downstream pathways, irrespective of the type of KIT primary or secondary mutation.
“While the function of this protein as a crucial effector of muscle atrophy in cachexia has been well described, its role and regulation in cancer remain controversial and have yet to be elucidated. Considering that GIST is grouped among tumors of muscular origin, we aimed to explore possible GIST-KIT molecular interplay,” said César Serrano co-corresponding author of this present study alongside Joaquín Arribas, Principal Investigator of VHIO’s Growth Factors Group, an ICREA Research Professor, and Director of the Hospital del Mar Medical Research (IMIM), Barcelona, Spain.
“Using different preclinical models, we observed that KIT-targeted inhibition leads to a significant increase in Atrogin-1. This overexpression is a specific survival mechanism of GIST cells, enabling the adaptation to KIT-directed inhibition by apoptosis evasion via cell quiescence,” added Alfonso García-Valverde, first author of this study and a Pre-Doctoral Fellow of César Serrano’s Group. Collectively, the study investigators have succeeded in unveiling the critical role of Atrogin-1 in GIST cell survival, regulation and biological function.
The signposting of next step directions
At present, there are no specific inhibitors targeting Atrogin-1, calling for the development of novel agents. The authors suggest that potential new therapies could be used in combination with imatinib as a more effective treatment strategy over current approaches.
In response, they propose the co-targeting of KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib. The researchers consequently performed in vitro and in vivo studies to assess the efficacy of combining imatinib with the TAK-243 small-molecule inhibitor of the ubiquitin activating enzyme.
“We observed that this therapeutic pairing effectively halted adaptation to treatment mediated by Atrogin-1, and led to significant increase in cancer cell death. This strategy points to a promising approach in maximizing the efficacy of currently available therapies in this patient population,” concluded César Serrano.
*García-Valverde A, Rosell J, Sayols S, Gómez-Peregrina D, Pilco-Janeta DF, Olivares-Rivas I, de Álava E, Maurel J, Rubió-Casadevall J, Esteve A, Gut M, Valverde C, Barretina J, Carles J, Demetri GD, Fletcher JA, Arribas J, Serrano C. E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor. Oncogene. 2021 Oct 7. doi: 10.1038/s41388-021-02049-0. Epub ahead of print. PMID: 34621020.