colorectal cancer Archives | Mikhail Blagosklonny Oncotarget

In a new study, researchers aimed to elucidate the role of cancer stemness in the resistance of colorectal cancer cells to targeted therapies.

Triple Combination Treatment Overcomes Colorectal Cancer Resistance

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Colorectal cancer is the third most diagnosed cancer and the second leading cause of cancer-related deaths worldwide. It often starts in the colon or rectum with small, noncancerous clumps of cells called polyps, which can develop into cancer over time. Risk factors for colorectal cancer include age, family history, inflammatory bowel diseases, diet, smoking, and physical activity.

The development and progression of colorectal cancer are driven by the aberrant activation of multiple signaling pathways, such as EGFR (epidermal growth factor receptor), RAS-RAF, and PTEN-PI3K. Among these pathways, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathways are particularly important, as they are frequently mutated in colorectal cancer. Therapeutic targeting of these pathways has shown promise in suppressing tumor growth. However, cancer cells often develop resistance to targeted therapies, leading to treatment failure and disease progression.

In a new study, researchers Astha Lamichhane, Gary D. Luker, Seema Agarwal, and Hossein Tavana from The University of Akron, University of Michigan and Georgetown University aimed to elucidate the role of cancer stemness in the resistance of colorectal cancer cells to targeted therapies. Their research paper was published in Oncotarget on October 4, 2023, entitled, “Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells.”

The Study

One of the major mechanisms of drug resistance in cancer is the gain of stemness in cancer cells under drug pressure. Cancer stem cells (CSCs) are a small subpopulation of cells within a tumor with the ability to self-renew and differentiate into various cell types that constitute the tumor. CSCs are thought to be responsible for tumor initiation, progression, and resistance to therapy. Therefore, identifying approaches to target CSCs is crucial for improving treatment outcomes in colorectal cancer patients.

In the current study, the researchers developed spheroid cultures of patient-derived BRAFmut and KRASmut tumor cells and studied the resistance mechanisms to inhibition of the MAPK pathway. The researchers found that treatment with MAPK pathway inhibitors enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated the PI3K/Akt pathway in cancer cells. These findings suggest that the development of drug resistance in colorectal cancer is associated with the acquisition of a stem cell-like phenotype.

To overcome drug resistance mediated by cancer stemness, the researchers examined various combination treatments to block these activities. They found that a triple combination treatment targeting BRAF, EGFR, and MEK significantly reduced stemness and the activities of oncogenic signaling pathways in colorectal cancer cells. This triple combination treatment has shown promise in clinical trials, with response rates of 21% and 32% in patients with BRAFmut colorectal cancer. The researchers demonstrated that this combination treatment effectively suppressed the growth, stemness, and activities of several oncogenic signaling pathways in cancer cells.

“Our finding supports the hypothesis that CSCs confer drug resistance and suppressing stemness is a viable approach in BRAFmut colorectal cancer.”

Conclusion

Altogether, the researchers found that inhibiting BRAF, EGFR, and MEK in combination shows promise in suppressing cancer stemness and overcoming drug resistance in colorectal cancer cells. This approach targets the underlying mechanisms of resistance, providing a potential strategy for improving treatment outcomes in patients with colorectal cancer. Further research and clinical trials are needed to validate the efficacy and safety of this triple combination therapy.

“In conclusion, this study presented a model of cyclic drug treatment and recovery of patient-derived tumor spheroids and established that single-agent MEK inhibition of colorectal cancer cells lead to adaptive resistance of cancer cells through gain of stemness. A triple combination treatment used in a clinical trial of colorectal cancer patients effectively blocked growth, stemness, and activities of several oncogenic signaling pathways in cancer cells. Our approach to identify mechanisms of drug resistance of patient-derived cancer cells to targeted therapies and develop effective treatments is promising toward cancer precision medicine.”

Click here to read the full research paper in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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In a new study, researchers investigated the creatine shuttle pathway as a potential therapeutic target in colorectal cancer cells.

Can the Creatine Shuttle be Targeted to Fight Colorectal Cancer?

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Since the 1992 Barcelona Olympics, creatine supplementation has increased in popularity and grown to widespread use among the mainstream public. Creatine is a naturally occurring compound, primarily stored in skeletal muscle and involved in energy production for high-intensity activities—enhancing performance and supporting muscle growth and strength. The process by which creatine is transported into the muscles and utilized for energy production is referred to as the creatine shuttle. While it is a useful mechanism for healthy muscles, the creatine shuttle has also been implicated in cancer.

“The creatine shuttle is highlighted in cancer as a source of energy for cancer cells that display aggressive proliferation, and aberrant creatine kinase (CK) levels are known to be associated with many malignancies and mitotic control [7].”

In a new study, researchers Mayu Kita, Rina Fujiwara-Tani, Shingo Kishi, Shiori Mori, Hitoshi Ohmori, Chie Nakashima, Kei Goto, Takamitsu Sasaki, Kiyomu Fujii, Isao Kawahara, Ujjal Kumar Bhawal, Yi Luo, and Hiroki Kuniyasu from Nara Medical University, Saveetha University and Nantong University hypothesized that the creatine shuttle is involved in energy metabolism and other adenosine triphosphate (ATP) supply in cancer cells. On May 19, 2023, their new research paper was published in Oncotarget’s Volume 14, entitled, “Role of creatine shuttle in colorectal cancer cells.”

“In the current study, the role of the creatine shuttle in CRC [colorectal cancer] was analyzed along with its potential as a therapeutic target.”

The Creatine Shuttle in Colorectal Cancer

Despite advancements in treatment options for colorectal cancer (CRC), incidence and mortality rates remain high. The metabolism of CRC cells is distinctly different from that of normal cells, and understanding these metabolic alterations is crucial for devising new targeted therapies. The creatine shuttle system plays a pivotal role in cellular energy metabolism, particularly in high-energy demanding tissues such as muscle and brain. However, its involvement in CRC cells has remained largely unexplored until now.

Creatine kinase, also known as CK or creatine phosphokinase, is an enzyme that catalyzes the transfer of a phosphate group from creatine phosphate to adenosine diphosphate (ADP), thereby regenerating adenosine triphosphate (ATP), which is the primary energy source for cells. CK exists in different forms or isoenzymes. In this study, the researchers investigated the expression and role of creatine kinase B (CKB) and mitochondrial creatine kinase (MTCK) in CRC tissues. They also explored the inhibitory effect of dinitrofluorobenzene (DNFB) on CKB and MTCK activity and its impact on CRC cell growth, stemness, mitochondrial function, energy metabolism, and cancer metastasis.

Inhibition of the Creatine Shuttle

The team used tissue arrays to examine CKB and MTCK expression in CRC tissues. Both proteins were highly expressed in high-grade tumors and cases with distant metastasis. Liver metastases showed higher expression compared to primary tumors, suggesting a role in CRC progression and metastasis.

DNFB, an inhibitor of CK activity, reduced CK activity and inhibited cell growth in CT26 and HT29 CRC cell lines. HT29 cells, with higher CKB and MTCK levels, were less sensitive to DNFB than CT26 cells. DNFB treatment decreased cell number, stem cell marker expression and impaired sphere formation in CT26 and HT29 cells. Knockdown of CKB or MTCK showed similar effects, indicating specificity to CK inhibition. DNFB also inhibited mitochondrial function and energy metabolism, decreasing mitochondrial membrane potential, increasing ROS production, and reducing OCR and ATP production in both cell lines.

In a mouse model of peritoneal dissemination, pretreatment with DNFB reduced tumor growth. Excised tumors from DNFB-treated mice showed decreased proliferation and stem cell marker expression, as well as reduced phosphorylation levels of tumor-promoting signaling molecules (EGFR, AKT, and ERK1/2).

Summary & Conclusion

“In this study, we showed that inhibition of the creatine shuttle by blocking CKB and MTCK activity suppressed the growth, stemness, and metastasis of cancer. It was suggested that the cause of this is related to inhibition of both mitochondrial energy metabolism and the phosphorylation signaling system.”

This research study provides valuable insights into the role of CKB and MTCK in CRC and highlights the therapeutic potential of inhibiting the creatine shuttle in CRC treatment. Inhibition of CKB and MTCK activity by DNFB impaired CRC cell growth, stemness, mitochondrial function, energy metabolism, and cancer metastasis. These findings suggest that targeting the creatine shuttle pathway may represent a promising therapeutic strategy for CRC patients. Further studies are warranted to validate these findings and explore the potential of targeting the creatine shuttle in clinical settings.

“Our data suggest that the antitumor effect of creatine shuttle inhibition can be attributed to the inhibition of mitochondrial energy production as well as the inhibition of multiple phosphorylation signals through inhibition of the ATP supply. Therefore, it is necessary to develop a new CK inhibitor to induce these two effects in vivo.”