Kras mutation subtypes distinctly affect colorectal cancer cell sensitivity to FL118, a novel inhibitor of survivin, Mcl-1, XIAP, cIAP2 and MdmX

Rabi Thangaiyan; Ieman Am Aljahdali; Kelsey Y Lent-Moore; Jianqun Liao; Xiang Ling; Fengzhi Li

Kras mutation subtypes distinctly affect colorectal cancer cell sensitivity to FL118, a novel inhibitor of survivin, Mcl-1, XIAP, cIAP2 and MdmX

Am J Transl Res. 2021 Jul 15;13(7):7458-7474. eCollection 2021.

Authors

Rabi Thangaiyan¹, Ieman Am Aljahdali^{1

2}, Kelsey Y Lent-Moore¹, Jianqun Liao^{1

3}, Xiang Ling^{1

3}, Fengzhi Li^{1

4}

Affiliations

¹ Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.
² Department of Cellular & Molecular Biology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.
³ Canget BioTekpharma LLC Buffalo, New York 14203, USA.
⁴ Developmental Therapeutics (DT) Program, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.

PMID: 34377229
PMCID: PMC8340187

Abstract

Mutation-activated Kras in cancer cells is a well-known challenging treatment-resistant factor that plays a critical role in treatment resistance. Human colorectal cancer (CRC) has four major Kras mutations; Kras^G12D (34.2%), Kras^G12V (21%), Kras^G13D (20%) and Kras^G12C (8.4%). Here, we report that while FL118 (a novel inhibitor of survivin, Mcl-1, XIAP, cIAP2 and MdmX) exhibits high efficacy to kill CRC cells and eliminate CRC tumors, CRC cells/tumors with different Kras mutation subtypes in the defined p53/APC genetic statuses exhibit different sensitivity to FL118 treatment. Using CRC cell lines, SW620 (Kras^G12V, mutant p53, mutant APC), DLD-1 (Kras^G13D, wild type p53, mutant APC) and SNU-C2B (Kras^G12D, mutant p53, wild type APC), we demonstrated that silencing of Kras^G12V and Kras^G12D using Kras-specific shRNA significantly increased CRC cell IC₅₀, while silencing of Kras^G13D decreased the CRC cell IC₅₀. This finding suggests that both Kras^G12V and Kras^G12D are required for showing higher FL118 efficacy, while the presence of Kras^G13D could somehow decrease FL118 efficacy under the defined p53/APC genetic status. Consistent with this notion, silencing of Kras^G12V in SW620 cells decreased FL118-induced apoptosis, while silencing of Kras^G13D in DLD-1 cells increased the FL118-induced apoptosis. Furthermore, forced expression of Kras^G12V in SW620 cells increased FL118-induced apoptosis, while forced expression of Kras^G13D in DLD-1 cells decreased FL118-induced apoptosis. Additionally, FL118 induced differential reactive oxygen species (ROS) production in SW620, DLD-1 and SNU-C2B cells. Our in vivo studies in animal models further confirmed that SW620 tumors are the most sensitive tumor to FL118 treatment; SNU-C2B tumors are the second most sensitive tumor to FL118 treatment; and the DLD-1 tumors are the least sensitive tumor. These findings would be useful for predicting FL118 sensitivity to patients' CRC tumors with the defined Kras mutation subtypes under the defined p53/APC genetic status.

Keywords: FL118; Mcl-1; MdmX; Mutant Kras; XIAP; cIAP2; colorectal cancer; human tumor animal model; survivin.

Abstract

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