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MUSC Fighting drug-resistant cancer by blocking an escape pathway

MUSC Health

Many cancer treatments such as chemotherapy and radiation kill cancer cells by inducing significant DNA damage beyond repair. But some tumors still develop alternative ways to survive. Now, scientists at the Medical University of South Carolina (MUSC) and Beth Israel Deaconess Medical Center have identified such a molecular pathway that helps cancer cells evade destruction.

The protein ECT2 is critical for the activation of a backup survival mechanism cancer cells resort to as part of their response to DNA damage, the scientists described in a study published in the journal Science Signaling.

As DNA damage response is essential for cell survival or death, better understanding of its mechanisms could lead to better combination therapies that can overcome tumor resistance, three researchers at the University of Illinois Chicago (UIC) said in an accompanying editorial.

Scientists know that the kinase AKT is a key regulator of genome stability—hence cell survival—by mediating downstream signaling involved in DNA damage response and DNA repair. Increased activation of the enzyme has been linked to cancer progression and resistance to drugs. However, the exact mechanisms of AKT activation in the face of DNA damage were unclear.

For its study, the MUSC and Beth Israel team treated multiple cancer cell lines with ionizing radiation or the chemotherapy etoposide and examined their responses. The researchers found that in response to drug-induced DNA damage, the DNA-PK enzyme modified a subunit of the mTORC2 protein complex.

ECT2 recognized that interaction and subsequently promoted AKT activation, according to the team. When ECT2 was removed in cancer cells, treatment with etoposide didn’t induce AKT activation. Compared with control cells, these ECT2-depleted cells responded better to etoposide, showing decreased colony formation.

What’s more, reintroducing ECT2 to the cells enhanced AKT activity, while an ECT2 mutant failed to do so, the team showed. Between the two groups, cells expressing normal ECT2 were less sensitive to etoposide partly because of reduced cell death.

A cancer patient may go through multiple lines of treatment as cancer cells outsmart the drugs they encounter. Many research groups are exploring ways to render resilient tumors vulnerable to existing treatment. Last year, two teams of scientists demonstrated the promising effects of inhibiting an enzyme called POLQ on BRCA-mutated tumors that had stopped responding to traditional PARP inhibitors.

A research team at the Swiss Federal Institute of Technology in Lausanne recently proposed adding CSF1R inhibition to control tumor-associated macrophages as a strategy to restore responses to the combination of PD-1/L1 immune checkpoint inhibitors, antiangiogenic drugs and chemo.   

“Targeting the [DNA damage response] in cancer is of great clinical importance to traditional, current and emerging therapies including immunotherapy given the observed induction of antitumor immunity by DDR-targeted therapies,” the UIC researchers wrote in the editorial. 

Findings from the current study pointed to combining DNA damage with DNA-PK-ECT2-mTORC2 network inhibition as a more efficient therapy against cancer, they said.

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Tamia Sumpter

Tamia is a driven senior undergraduate Bioengineering student currently enrolled at Clemson University. With a strong foundation in her field, she has honed her skills through hands-on experience in research and development at Eli Lilly & Company. During her time in the ADME department, Tamia contributed significantly by working on siRNAs and their applications in finding In Vitro-In Vivo Correlation (IVIVC). Looking ahead, Tamia has set her sights on a promising career in law. She aspires to specialize in Intellectual Property Law, with a particular focus on serving as in-house counsel for leading medical device or pharmaceutical companies. Her enthusiasm for this role is palpable as she prepares to embark on her legal journey! She is also a proud member of the Omicron Phi chapter of Delta Sigma Theta Sorority, Inc., PEER Mentor for Clemson PEER/WiSE, and currently serves as the President of Clemson Bioengineering Organization (CBO). With her unique blend of scientific knowledge and legal interests, Tamia is poised to make a meaningful impact in the healthcare and life sciences industries.