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PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin ?₃-KRAS-dependent pancreatic cancer stem cells.

ABSTRACT: Today, pancreatic cancer (PC) remains a major health problem in the US. The fact that cancer stem cells (CSCs) become enriched in humans following anti-cancer therapy implicates CSCs as key contributors to tumor dormancy, metastasis, and relapse in PC. A highly validated CSC model (FG?₃ cells) was used to test a novel compound (PAWI-2) to eradicate CSCs. Compared to parental bulk FG cells, PAWI-2 showed greater potency to inhibit cell viability and self-renewal capacity of FG?₃ cells. For FG?₃ cells, dysregulated integrin ?₃-KRAS signaling drives tumor progression. PAWI-2 inhibited ?₃-KRAS signaling independent of KRAS. This is clinically relevant. PAWI-2 targeted the downstream TBK1 phosphorylation cascade that was negatively regulated by optineurin phosphorylation via a feedback mechanism. This was confirmed by TBK1 genetic knockdown or co-treatment with TBK1-specific inhibitor (MRT67307). PAWI-2 also overcame erlotinib (an EGFR inhibitor) resistance in FG?₃ cells more potently than bortezomib. In the proposed working model, optineurin acts as a key regulator to link inhibition of KRAS signaling and cell cycle arrest (G2/M). The findings show PAWI-2 is a new approach to reverse tumor stemness that resensitizes CSC tumors to drug inhibition.

SUBMITTER: Cheng J

PROVIDER: S-EPMC7280251 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin β3-KRAS-dependent pancreatic cancer stem cells.

Cheng Jiongjia J Cashman John R JR

Scientific reports 20200608 1

Today, pancreatic cancer (PC) remains a major health problem in the US. The fact that cancer stem cells (CSCs) become enriched in humans following anti-cancer therapy implicates CSCs as key contributors to tumor dormancy, metastasis, and relapse in PC. A highly validated CSC model (FGβ3 cells) was used to test a novel compound (PAWI-2) to eradicate CSCs. Compared to parental bulk FG cells, PAWI-2 showed greater potency to inhibit cell viability and self-renewal capacity of FGβ3</ ...[more]

PMID: 32514015

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Project description:BACKGROUND:Pancreatic cancer is a deadly disease with a very low 5-year patient survival rate of 6-8%. The major challenges of eliminating pancreatic cancer are treatment resistance and stromal barriers to optimal drug access within the tumor. Therefore, effective molecular targeting drugs with high intra-tumor access and retention are urgently needed for managing this devastating disease in the clinic. METHODS:This study has used the following in vitro and in vivo techniques for the investigation of exceptional anticancer drug FL118's efficacy in treatment of resistant pancreatic cancer: cell culture; immunoblotting analysis to test protein expression; DNA sub-G1 flow cytometry analyses to test cell death; MTT assay to test cell viability; pancreatic cancer stem cell assays (fluorescence microscopy tracing; matrigel assay; CD44-positive cell colony formation assay); human luciferase-labeled pancreatic tumor orthotopic animal model in vivo imaging; pancreatic cancer patient-derived xenograft (PDX) animal models; and toxicology studies with immune-competent BALB/cj mice and beagle dogs. RESULTS:Our studies found that FL118 alone preferentially killed cisplatin-resistant cancer cells, while a combination of FL118 with cisplatin synergistically killed resistant pancreatic cancer cells and reduced spheroid formation of treatment-resistant pancreatic cancer stem-like cells. Furthermore, using in vivo-imaging, we found that FL118 in combination with cisplatin strongly inhibited both drug-resistant pancreatic xenograft tumor growth and metastasis. In PDX model, we demonstrated that FL118 alone effectively eliminated PDX tumors, while FL118 in combination with gemcitabine eliminated PDX tumors that showed relative resistance (less sensitivity) to treatment with FL118. These FL118 efficacy results are consistent with our molecular-targeting data showing that FL118 inhibited the expression of multiple antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and ERCC6, a critical regulator of DNA repair, in treatment-resistant pancreatic stem-like cancer cells. Furthermore, FL118 toxicity studies in BALB/cj mice and beagle dogs indicated that FL118 exhibits favorable hematopoietic and biochemical toxicities. CONCLUSION:Together, our studies suggest that FL118 is a promising anticancer drug for further clinical development to effectively treat drug-resistant pancreatic cancer alone or in combination with other pancreatic cancer chemotherapeutic drugs.

Dataset Information

PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin ?₃-KRAS-dependent pancreatic cancer stem cells.

Publications

PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin β<sub>3</sub>-KRAS-dependent pancreatic cancer stem cells.

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Dataset Information

PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin ?3-KRAS-dependent pancreatic cancer stem cells.

Publications

PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin β<sub>3</sub>-KRAS-dependent pancreatic cancer stem cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin ?₃-KRAS-dependent pancreatic cancer stem cells.