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Use of a KIT-specific monoclonal antibody to bypass imatinib resistance in gastrointestinal stromal tumors.

Edris B, Willingham S, Weiskopf K, Volkmer AK, Volkmer JP, M├╝hlenberg T, Weissman IL, van de Rijn M - Oncoimmunology (2013)

Bottom Line: Acquired resistance to imatinib is a significant problem for the clinical management of gastrointestinal stromal tumor (GIST) patients, and second-line small molecules have shown limited efficacy in this setting.We have recently demonstrated that a monoclonal antibody targeting KIT could potentially bypass imatinib resistance in preclinical models of GIST.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology; Stanford University School of Medicine; Stanford, CA USA ; Department of Genetics; Stanford University School of Medicine; Stanford, CA USA.

ABSTRACT
Acquired resistance to imatinib is a significant problem for the clinical management of gastrointestinal stromal tumor (GIST) patients, and second-line small molecules have shown limited efficacy in this setting. We have recently demonstrated that a monoclonal antibody targeting KIT could potentially bypass imatinib resistance in preclinical models of GIST.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Use of a monoclonal antibody to bypass imatinib resistance in gastrointestinal stromal tumors. (A) Mutations (X) in KIT constitutively activate the KIT pathway but leave gastrointestinal stromal tumor (GIST) cells sensitive to the antineoplastic effects of imatinib. (B) Nevertheless, GIST cells eventually develop secondary KIT mutations (Y) that enable them to proliferate in the presence of imatinib. (C) We have recently shown that SR1, an anti-KIT monoclonal antibody (mAb), can inhibit the growth of GIST cells that have become resistant to imatinib and enable their clearance by immune effector mechanisms. (D) In the future, a combinatorial regimen involving a second mAb, for instance targeting CD47, may turn out to further enhance the therapeutic effects of SR1.
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Figure 1: Figure 1. Use of a monoclonal antibody to bypass imatinib resistance in gastrointestinal stromal tumors. (A) Mutations (X) in KIT constitutively activate the KIT pathway but leave gastrointestinal stromal tumor (GIST) cells sensitive to the antineoplastic effects of imatinib. (B) Nevertheless, GIST cells eventually develop secondary KIT mutations (Y) that enable them to proliferate in the presence of imatinib. (C) We have recently shown that SR1, an anti-KIT monoclonal antibody (mAb), can inhibit the growth of GIST cells that have become resistant to imatinib and enable their clearance by immune effector mechanisms. (D) In the future, a combinatorial regimen involving a second mAb, for instance targeting CD47, may turn out to further enhance the therapeutic effects of SR1.

Mentions: First, we demonstrated that SR1 is able to slow the growth of three primary human GIST cell lines (two of which deriving from patients that had developed imatinib resistance) in vitro. Importantly, the reduction of cell viability observed in the presence of SR1 was equivalent in imatinib-sensitive and -resistant cell lines. Besides blocking signal transduction, mAbs targeting cell surface proteins can also enable robust antitumor innate immune responses. Therefore, we next evaluated whether SR1 would operate as an opsonin and allow macrophages to engulf GIST cells in vitro. We found that the binding of SR1 to KIT-expressing tumor cells increased their phagocytic uptake by macrophages, irrespective of their original sensitivity to imatinib (Fig. 1).


Use of a KIT-specific monoclonal antibody to bypass imatinib resistance in gastrointestinal stromal tumors.

Edris B, Willingham S, Weiskopf K, Volkmer AK, Volkmer JP, M├╝hlenberg T, Weissman IL, van de Rijn M - Oncoimmunology (2013)

Figure 1. Use of a monoclonal antibody to bypass imatinib resistance in gastrointestinal stromal tumors. (A) Mutations (X) in KIT constitutively activate the KIT pathway but leave gastrointestinal stromal tumor (GIST) cells sensitive to the antineoplastic effects of imatinib. (B) Nevertheless, GIST cells eventually develop secondary KIT mutations (Y) that enable them to proliferate in the presence of imatinib. (C) We have recently shown that SR1, an anti-KIT monoclonal antibody (mAb), can inhibit the growth of GIST cells that have become resistant to imatinib and enable their clearance by immune effector mechanisms. (D) In the future, a combinatorial regimen involving a second mAb, for instance targeting CD47, may turn out to further enhance the therapeutic effects of SR1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3716740&req=5

Figure 1: Figure 1. Use of a monoclonal antibody to bypass imatinib resistance in gastrointestinal stromal tumors. (A) Mutations (X) in KIT constitutively activate the KIT pathway but leave gastrointestinal stromal tumor (GIST) cells sensitive to the antineoplastic effects of imatinib. (B) Nevertheless, GIST cells eventually develop secondary KIT mutations (Y) that enable them to proliferate in the presence of imatinib. (C) We have recently shown that SR1, an anti-KIT monoclonal antibody (mAb), can inhibit the growth of GIST cells that have become resistant to imatinib and enable their clearance by immune effector mechanisms. (D) In the future, a combinatorial regimen involving a second mAb, for instance targeting CD47, may turn out to further enhance the therapeutic effects of SR1.
Mentions: First, we demonstrated that SR1 is able to slow the growth of three primary human GIST cell lines (two of which deriving from patients that had developed imatinib resistance) in vitro. Importantly, the reduction of cell viability observed in the presence of SR1 was equivalent in imatinib-sensitive and -resistant cell lines. Besides blocking signal transduction, mAbs targeting cell surface proteins can also enable robust antitumor innate immune responses. Therefore, we next evaluated whether SR1 would operate as an opsonin and allow macrophages to engulf GIST cells in vitro. We found that the binding of SR1 to KIT-expressing tumor cells increased their phagocytic uptake by macrophages, irrespective of their original sensitivity to imatinib (Fig. 1).

Bottom Line: Acquired resistance to imatinib is a significant problem for the clinical management of gastrointestinal stromal tumor (GIST) patients, and second-line small molecules have shown limited efficacy in this setting.We have recently demonstrated that a monoclonal antibody targeting KIT could potentially bypass imatinib resistance in preclinical models of GIST.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology; Stanford University School of Medicine; Stanford, CA USA ; Department of Genetics; Stanford University School of Medicine; Stanford, CA USA.

ABSTRACT
Acquired resistance to imatinib is a significant problem for the clinical management of gastrointestinal stromal tumor (GIST) patients, and second-line small molecules have shown limited efficacy in this setting. We have recently demonstrated that a monoclonal antibody targeting KIT could potentially bypass imatinib resistance in preclinical models of GIST.

No MeSH data available.


Related in: MedlinePlus