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Ref Type Journal Article
PMID (32371592)
Authors García-Valverde A, Rosell J, Serna G, Valverde C, Carles J, Nuciforo P, Fletcher JA, Arribas J, Politz O, Serrano C
Title Preclinical Activity of PI3K Inhibitor Copanlisib in Gastrointestinal Stromal Tumor.
Journal Molecular cancer therapeutics
Vol 19
Issue 6
Date 2020 06
URL
Abstract Text 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. In vitro 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 in vivo, 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V560_Y578del gastrointestinal stromal tumor sensitive Copanlisib + Imatinib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Aliqopa (copanlisib) and Gleevec (imatinib) demonstrated enhanced cell growth inhibition and increased apoptosis of gastrointestinal stromal tumor cells harboring KIT V560_Y578del in culture and in cell line xenograft models (PMID: 32371592). 32371592
KIT V560_Y578del gastrointestinal stromal tumor sensitive Copanlisib Preclinical - Cell line xenograft Actionable In a preclinical study, Aliqopa (copanlisib) inhibited cell growth and PI3K signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture, and inhibited tumor growth in cell line xenograft models (PMID: 32371592). 32371592
KIT V560_Y578del KIT T670I gastrointestinal stromal tumor predicted - sensitive Copanlisib + Imatinib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Aliqopa (copanlisib) and Gleevec (imatinib) demonstrated enhanced cell growth inhibition but did not result in increased apoptosis of gastrointestinal stromal tumor cells harboring KIT V560_Y578del and KIT T670I in culture, and did not result in increased tumor growth inhibition compared to Aliqopa (copanlisib) alone in cell line xenograft models (PMID: 32371592). 32371592
KIT V560_Y578del KIT T670I gastrointestinal stromal tumor sensitive Copanlisib Preclinical - Cell line xenograft Actionable In a preclinical study, Aliqopa (copanlisib) inhibited cell growth and PI3K signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT T670I in culture, and inhibited tumor growth in cell line xenograft models (PMID: 32371592). 32371592
KIT exon11 KIT V654A gastrointestinal stromal tumor sensitive Copanlisib Preclinical - Cell culture Actionable In a preclinical study, Aliqopa (copanlisib) inhibited cell growth and PI3K signaling in a gastrointestinal stromal tumor cell line harboring a KIT exon 11 deletion and KIT V654A in culture (PMID: 32371592). 32371592
KIT exon11 KIT V654A gastrointestinal stromal tumor predicted - sensitive Copanlisib + Imatinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Aliqopa (copanlisib) and Gleevec (imatinib) demonstrated enhanced cell growth inhibition but did not result in increased apoptosis of gastrointestinal stromal tumor cells harboring a KIT exon 11 deletion and KIT V654A compared to either agent alone in culture (PMID: 32371592). 32371592