New targets and therapies for gastrointestinal stromal tumors

ABSTRACT

Introduction: The majority of gastrointestinal stromal tumors (GIST) are driven by an abnormal receptor tyrosine kinase (RTK) signaling, occurring mainly due to somatic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA). Although the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized therapy for GIST patients, with time the vast majority of them develop TKI resistance. Advances in understanding the molecular background of GIST resistance allows for the identification of new targets and the development of novel strategies to overcome or delay its occurrence.

Areas covered: The focus of this review is on novel, promising therapeutic approaches to overcome heterogeneous resistance to registered TKIs. These approaches involve new TKIs, including drugs specific for a mutated form of KIT/PDGFRA, drugs with inhibitory effect against multiple RTKs, compounds targeting dysregulated downstream signaling pathways, drugs affecting KIT expression and degradation, inhibitors of cell cycle, and immunotherapeutics.

Expert commentary: As the resistance to standard TKI treatment can be heterogeneous, a combinational approach for refractory GIST could be beneficial. Moreover, the understanding of the molecular background of resistant disease would allow development of a more personalized approach for these patients and their response to targeted therapy could be monitored closely using ‘liquid biopsy’.

KEYWORDS:

• Gastrointestinal stromal tumors
• KIT
• platelet derived growth factor receptor alpha
• tyrosine kinase inhibitors
• resistance
• targeted therapy

Declaration of interest

P. Schoffski has received honoraria from Eli Lilly and Novartis. He has also acted in a consultant or advisory role for AstraZeneca, Bayer, Blueprint Medicines, Bristol-Meyers Squibb, Eli Lilly, Novartis, and Plexxikon. He has been part of the speaker’s bureau for Bayer, Eli Lilly, GlaxoSmithKline and Novartis, and have received research funding from Bayer, Blueprint Medicines, Exelixis, GlaxoSmithKline, Novartis, and Plexxikon. He has received travel and accommodation expenses from AstraZeneca, Bayer, Blueprint Medicines, Bristol-Meyers Squibb, Eli Lilly, GlaxoSmithKline, Novartis, and Plexxikon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

A reviewer on this manuscript has disclosed that they have received speaker’s honoraria from Novartis. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.