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Image: Mattias Pettersson

Kjell Grankvist lab

Research group Methods for breaking cisplatin resistance in lung cancer treatment.

Treatment of patients with advanced stages of lung cancer is most often done with the cytotoxic drug cisplatin, although very specific immunotherapies have also been developed. Resistance to treatment arises in most cases, which means that chemotherapy of the patient's tumor often fails.

Through protein-level studies, we have identified three central and pharmacologically influential signaling mechanisms for cell death in cultured tumor cells, which provide therapeutic possibilities for these difficult-to-treat tumors.

We study the apoptosis signaling pathways for acquired cisplatin resistance through analyzes of several types of cultured tumor cells from non-small cell lung cancer, with and without induced cisplatin resistance. In most tumors, the cell membranes express heat-shock proteins (especially HSP70) that protect the active proteins of the tumor cells against misfolding and degradation and have a general inhibition of cell death (apoptosis) so that the treatment resistance increases and the tumor grows. At the same time, the glycolipid Gb3 is expressed, which is located block by block with HSP70.

Gb3 is the result of the toxic substance ceramide, which is normally formed in the cell and participates in cell death in sensitive tumor cells, instead being converted to harmless Gb3 and thus loses its cell-killing effect. There are a number of clinical studies that have attempted to inhibit the cell membrane's expression of HSP70 to remove its protective effect on tumor cells. However, this has not been successful so there are currently no effective and side-effect-free HSP70 inhibitors for clinical treatment.

We have shown that a toxin that binds to Gb3 or if you use inhibitors that stop the formation of Gb3, the lung cancer cells regain their sensitivity to cisplatin again due to the fact that HSP70 is also knocked out in parallel with Gb3. We investigate whether this is a general mechanism in lung cancer cells by using flow cytometry and microscopy to study several types of lung cancer cells that we made cisplatin resistant with the original cells before the development of resistance.

Then we can see if it is always the case that HSP70 and closely related proteins that are located with each other in the cell membrane are eliminated together with agents that also reduce the expression of Gb3 on the surface of the tumor cells. Unlike HSP70 inhibitors that have been tested, there are Gb3 inhibitors that have already been given to patients with no or minimal side effects.

Lung cancer is a very difficult-to-treat tumor form where new treatment options are needed. Our research may lead to the development of new treatment options for lung cancer.

Head of research

Kjell Grankvist
Professor
E-mail
Email

Overview

Participating departments and units at Umeå University

Department of Medical Biosciences

Research area

Cancer
Latest update: 2022-04-25