Dealing with the “hammer to fall”: a precise target to be struck for an optimal cell killing

Lung cancer accounts for a quarter of all cancer deaths, and non-small cell lung cancer makes up 84% of all lung cancer cases. Targeted therapies can be effective for a time against selected lung cancers, but resistance to these therapies soon develops. A cancer cell is like a small factory with many moving parts working towards one common goal: survival and reproduction of the tumor at the expense of the patient. A type of targeted drug, called tyrosine kinase inhibitors, or TKIs, work by inhibiting a specific, vital protein within the cell factory on which it is dependent. However, the factory has many fail-safes in place and can quickly rely on another piece of cellular machinery to continue to grow and survive, even in the presence of the TKI. The ability of a cancer cell to adapt to a new strategy to survive is called “genetic resistance”. When researchers developed TKIs for the treatment of cancers such as non-small cell lung adenocarcinoma (NSCLC), they had hoped they would become the longly hoped “magic bullet”.

One of the benefits of TKIs is that they’re much less toxic and are fairly beneficial — we see a dramatic response and the tumors shrink. But a limitation is that these effects don’t last very long before the cancer cells evolve new techniques to become resistant to the drug. Due to such resistance, the survival outcomes for patients receiving TKIs are no better than those for patients receiving conventional chemotherapy. Consequently, the need to find treatments that can overcome that resistance is urgent. Now a team of researchers at the Medical University of South Carolina reported that a protein highly expressed in lung cancer cells drives resistance to targeted therapies. In preclinical experiments, the researchers showed that inhibiting the protein caused the death of non-small cell lung cancer cells that had become resistant to therapy. The team was led by Chadrick E. Denlinger, MD, an professor Robert Gemmill, PhD, in the Department of Medicine.

Recently, the team linked drug resistance in lung cancers to the expression of a cell surface co-receptor Neuropilin 2 (NRP2). One of the earliest things they discovered was that the NRP2 variant protein, NRP2b, dramatically increased in lung cancer patients who became resistant to therapy. This gave them the first clue that it becomes upregulated in resistant tumors. The investigators then performed a series of experiments in which they “knocked down” NRP2b from lung cancer cell lines that were capable of developing TKI resistance. Once they knock down NRP2b, the surviving drug-tolerant cells got lost. And scientists believe that by reducing that population, tehy will reduce the ability of the tumor to develop genetic resistance. Next, they explored how NRP2b could be contributing to drug resistance in lung cancer cells. They started with GSK3, a protein kinase that has been reported previously to interact with NRP2b during neuronal development.

The investigators performed experiments to determine whether NRP2b interacts with GSK3B. Professor Gemmil brought a practical example of these proteins: “You can think about GSK3B as a hammer. And this hammer has the job of hammering many different nails that are present in the cell. NRP2b is like the hand of the carpenter that directs that hammer to particular nails. NRP2b is using GSK3B as a hammer to drive very specific nails, and we want to stop that because those nails are driving tumor progression”. To better understand the specific nails that NRP2b and GSK3B are driving in lung cancer, the investigators performed experiments in which they measured how well lung cancer cells can migrate and survive in the presence of TKIs in the absence of these two players. With these experiments, they found that NRP2b needs GSK3B to promote cancer cell migration, an essential step in cancer progression, and drug resistance.

Now that the investigators have identified a mechanism by which cancer cells are becoming resistant to treatment, their next step will involve developing inhibitors. More specifically, they will try to develop inhibitors that interfere with the carpenter (NRP2) grabbing the hammer (GSK3B). Importantly, these inhibitors should not interfere with other functions of GSK3B, which will reduce potentially harmful off-target effects in a healthy cell. Currently, the team is working to test the toxicity and effectiveness of prototype drugs that could specifically disrupt the interaction between GSK3B and NRP2b. That would be an absolute novelty, because while there are several inhibitors of GSK3B, there is no known molecule that interrupts its interaction with other targets.

  • Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.

Scientific references

Dimou A et al. J Thorac Cardiovasc Surg 2020 May 25.

Dimou A, Syrigos KN. Front Oncol. 2020 Jul 24; 10:1221. 

Patil T, Pacheco JM et al. Front Oncol. 2020 Apr; 10:510. 

Dimou A, Camidge DR. Clin Cancer Res. 2019; 25(16):4865. 

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Informazioni su Dott. Gianfrancesco Cormaci 2449 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it
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