Preclinical Activity of PI3K Inhibitor Copanlisib in Gastrointestinal Stromal Tumor

KIT or PDGFRA gain-of-function mutations are the primary drivers of gastrointestinal stromal tumor (GIST) growth and progression throughout the disease course. The PI3K/mTOR pathway is critically involved in the transduction of KIT/PDGFRA oncogenic signaling regardless of the type of primary and sec...

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Published in:Molecular cancer therapeutics 2020-06, Vol.19 (6), p.1289-1297
Main Authors: García-Valverde, Alfonso, Rosell, Jordi, Serna, Garazi, Valverde, Claudia, Carles, Joan, Nuciforo, Paolo, Fletcher, Jonathan A, Arribas, Joaquín, Politz, Oliver, Serrano, César
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cell Proliferation
Drug Resistance, Neoplasm - drug effects
Female
Gastrointestinal Neoplasms - drug therapy
Gastrointestinal Neoplasms - enzymology
Gastrointestinal Neoplasms - pathology
Gastrointestinal Stromal Tumors - drug therapy
Gastrointestinal Stromal Tumors - enzymology
Gastrointestinal Stromal Tumors - pathology
Humans
Imatinib Mesylate - pharmacology
Mice
Mice, Nude
Phosphatidylinositol 3-Kinases - chemistry
Protein Kinase Inhibitors - pharmacology
Pyrimidines - pharmacology
Quinazolines - pharmacology
Signal Transduction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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Summary:KIT or PDGFRA gain-of-function mutations are the primary drivers of gastrointestinal stromal tumor (GIST) growth and progression throughout the disease course. The PI3K/mTOR pathway is critically involved in the transduction of KIT/PDGFRA oncogenic signaling regardless of the type of primary and secondary mutations, and therefore emerges as a relevant targetable node in GIST biology. We evaluated in GIST preclinical models the antitumor activity of copanlisib, a novel pan-class-I PI3K inhibitor with predominant activity against p110α and p110δ isoforms, as single-agent and in combination with first-line KIT inhibitor imatinib. studies undertaken in one imatinib-sensitive (GIST-T1) and two imatinib-resistant (GIST-T1/670 and GIST430/654) GIST cell models showed that single-agent copanlisib effectively suppressed PI3K pathway activation leading to decreased cell viability and proliferation in both imatinib-sensitive and -resistant cells irrespective of the type of primary or secondary KIT mutations. Simultaneous PI3K and KIT inhibition with copanlisib and imatinib resulted in enhanced impairment of cell viability in both imatinib-sensitive and -resistant GIST cell models, although apoptosis was mostly triggered in GIST-T1. Single-agent copanlisib inhibited GIST growth , and conjoined inhibition of PI3K and KIT was the most active therapeutic intervention in imatinib-sensitive GIST-T1 xenografts. IHC stain for cleaved-caspase 3 and phospho-S6 support a predominant antiproliferative effect of copanlisib in GIST. In conclusion, copanlisib has single-agent antitumor activity in GIST regardless KIT mutational status or sensitivity to imatinib. Effective KIT inhibition is necessary to achieve synergistic or additive effects with the combination of imatinib and any given PI3K/mTOR pathway inhibition.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-19-1069