Inhibitor of the Nuclear Transport Protein XPO1 Enhances the Anticancer Efficacy of KRAS G12C Inhibitors in Preclinical Models of KRAS G12C–Mutant Cancers

Khan, Husain Yar; Nagasaka, Misako; Li, Yiwei; Aboukameel, Amro; Uddin, Md. Hafiz; Sexton, Rachael; Bannoura, Sahar; Mzannar, Yousef; Hallak, Mohammed Najeeb Al; Kim, Steve; Beydoun, Rafic; Landesman, Yosef; Mamdani, Hirva; Uprety, Dipesh; Philip, Philip A.; Mohammad, Ramzi M.; Shields, Anthony F.; Azmi, Asfar S.

doi:10.1158/2767-9764.crc-21-0176

Cited by 18 publications

(16 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is a growing understanding of the importance of identifying synthetic lethality associated with KRAS and developing small molecule inhibitors that target these synthetic lethal targets. Previously, we had experimentally validated synthetic lethal interactions of KRASG12C inhibitors with nuclear export protein XPO1 inhibitor in silico, in vitro and in vivo [26]. In this study, the identification of the existence of synthetic lethality between PAK4 and KRAS using the Slorth database rationalizes the significance of co-targeting PAK4 and KRAS.…”

Section: Discussionmentioning

confidence: 91%

“…Previously, we had experimentally validated synthetic lethal interactions of KRASG12C inhibitors with nuclear export protein XPO1 inhibitor in silico, in vitro and in vivo [26]. In this study, the identification of the existence of synthetic lethality between PAK4 and KRAS using the Slorth database rationalizes the significance of co-targeting PAK4 and KRAS.…”

Section: Discussionmentioning

confidence: 93%

“…KRASG12C inhibitor-resistant cell lines were generated in our lab as described previously [26]. To establish the durability of drug-resistance, we compared the IC 50 values of sotorasib-resistant cell line (MIA-AMG-R) that we developed earlier with the sotorasib-sensitive parental cell line (MIA PaCa-2).…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers

Khan

Nagasaka

Aboukameel

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

KRASG12C inhibitors have revolutionized the treatment landscape for cancer patients harboring the G12C mutant isoform of KRAS. With the recent FDA approval of sotorasib and adagrasib, patients now have access to more promising treatment options. However, patients who receive these agents as a monotherapy usually develop drug resistance. Thus, there is a need to develop logical combination strategies that can delay or prevent the onset of resistance and simultaneously enhance the antitumor effectiveness of the treatment regimen. In this study, we aimed at pharmacologically targeting PAK4 by KPT9274 in combination with KRASG12C inhibitors in KRASG12C mutant pancreatic ductal adenocarcinoma (PDAC) and nonsmall cell lung cancer (NSCLC) preclinical models. PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We assessed the cytotoxicity of PAK4 and KRASG12C inhibitors combination in KRASG12C mutant 2D and 3D cellular models. KPT9274 synergized with both sotorasib and adagrasib in inhibiting the growth of KRASG12C mutant cancer cells. The combination was able to reduce the clonogenic potential of KRASG12C mutant PDAC cells. We also evaluated the antitumor activity of the combination in a KRASG12C mutant PDAC cell line derived xenograft (CDX) model. Oral administration of a suboptimal dose of KPT9274 in combination with sotorasib (at one fourth of MTD) demonstrated significant inhibition of the tumor burden (p = 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model where KPT9274, acting as an adjuvant, prevented tumor relapse following the discontinuation of sotorasib treatment (p = 0.0001). KPT9274 and sotorasib combination also resulted in enhanced survival. This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitor KPT9274 both in vitro and in vivo resulting in remarkably enhanced antitumor activity and survival outcomes.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers

Khan

Nagasaka

Aboukameel

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, the combined targeting of KRAS G12C with cell cycle checkpoints or immune checkpoints is promising [ 50 , 72 , 117 ]; the triple combined inhibition of KRAS G12C /SHP2/PD-L1 leads to severe tumor regression in PDAC mouse models [ 108 ]. Recent studies have shown that the nuclear export protein exportin 1 (XPO1) relieves tumor cells from resistance to KRAS G12C inhibitors [ 118 ]. This effect has been demonstrated in a mouse xenograft model.…”

Section: Strategies To Circumvent Drug Resistancementioning

confidence: 99%

Targeting KRAS in PDAC: A New Way to Cure It?

Liu

Wang

2022

Cancers

View full text Add to dashboard Cite

Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory nature and poor prognosis. The fatality rate of pancreatic cancer can reach over 90%. In pancreatic ductal carcinoma (PDAC), the most common subtype of pancreatic cancer, KRAS is the most predominant mutated gene (more than 80%). In recent decades, KRAS proteins have maintained the reputation of being “undruggable” due to their special molecular structures and biological characteristics, making therapy targeting downstream genes challenging. Fortunately, the heavy rampart formed by KRAS has been broken down in recent years by the advent of KRASG12Cinhibitors; the covalent inhibitors bond to the switch-II pocket of the KRASG12Cprotein. The KRASG12C inhibitor sotorasib has been received by the FDA for the treatment of patients suffering from KRASG12C-driven cancers. Meanwhile, researchers have paid close attention to the development of inhibitors for other KRAS mutations. Due to the high incidence of PDAC, developing KRASG12D/V inhibitors has become the focus of attention. Here, we review the clinical status of PDAC and recent research progress in targeting KRASG12D/V and discuss the potential applications.

show abstract

“…5,6 Selinexor is a first-in-class, selective inhibitor of nuclear export and binds covalently to Exportin 1. 3,7,8 Studies have demonstrated that selective inhibitors of nuclear export can block the growth of both NSCLC cell lines and xenografts alone, 9 and with targeted agents, such as the KRAS G12C inhibitors, 10 Bcl-xL inhibitor A-1331852, 11 poly(ADP-ribose) polymerase inhibitor BMN673 (12), and chemotherapeutic agents such as cisplatin. 13 It has been shown to reduce the protein levels of driver oncogenes, such as MYC and EGFR, in multiple cancer types.…”

Section: Introductionmentioning

confidence: 99%

Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non–small cell lung cancer

Altan

Milton

et al. 2023

Cancer

View full text Add to dashboard Cite

BackgroundIn lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell‐cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non–small cell lung cancer (mNSCLC).MethodsThe primary objective of this prospective investigator‐initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression‐free survival duration.ResultsA total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti–PD‐1/programmed death‐ligand 1 (PD‐L1) therapy. The median age was 67.5 years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti–PD‐1/PD‐L1 therapy and in patients with activating driver mutations. The median overall survival and progression‐free survival were 11.4 months (95% CI, 3.4–19.8 months) and 3.0 months (95% CI, 1.7–5.7 months), respectively. The overall response rate was 18% and the 6‐month disease control rate was 24%.ConclusionsSelinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti–PD‐1/PD‐L1 therapy. The therapy‐related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed.Trial registrationClinicalTrials.gov identifier: NCT02419495.Plain language summary New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor‐suppressing pathways and induce potent immunomodulatory activities. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non–small cell lung cancer.

show abstract

Inhibitor of the Nuclear Transport Protein XPO1 Enhances the Anticancer Efficacy of KRAS G12C Inhibitors in Preclinical Models of KRAS G12C–Mutant Cancers

Cited by 18 publications

References 39 publications

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers

Targeting KRAS in PDAC: A New Way to Cure It?

Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non–small cell lung cancer

Contact Info

Product

Resources

About