A new approach that targets different cancer cell groups within single tumors based on their respective sensitivities to a drug is reported in the scientific journal Nature Medicine on January 15. Researchers suggest that this can be an innovative strategy against resistant cancers.
Background
Tumours often comprise of groups of cancer cells that show different sensitivities to the same drug. This is one of the reasons why sometimes the initial effectiveness of treatments does not last in some patients.
Cells sensitive to a drug therapy are eliminated, but those less sensitive to the same drug continue to grow, shortening the duration of clinical response. Tumours can therefore develop resistance over time to the drugs used.
For example, melanomas, the most aggressive type of skin cancer, often carry a mutation in the BRAF-gene, which causes the tumour cells to proliferate. This can be effectively treated by a tailored treatment using a BRAF-inhibitor.
Unfortunately, tumours can develop resistance to this drug, even when it is combined with a MEK-inhibitor, which hits the same signaling pathway to block the protein involved in cancer cell growth and survival.
Targeting this kind of cancer resistance, researchers from the Netherlands Cancer Institute in Amsterdam, in collaboration with biotechnology company Genmab A/S, have developed a new approach.
New strategy
The research group at the Netherlands Cancer Institute led by Prof. Daniel Peeper had previously discovered that such resistant melanomas start producing another protein, AXL. The AXL- protein sits on the outside of the tumour cell and therefore constitutes, in principle, a good target for treatment.
On the other hand, biotechnology Genmab A/S had already developed a product called HuMax-AXL-ADC, which specifically binds to and kills tumour cells expressing the AXL-protein.
A researcher at the cancer institute laboratory, PhD student Julia Boshuizen, discovered that melanomas that were resistant to BRAF- and MEK-inhibitors indeed harboured a large number of AXL-high cells.
However, most tumours still contained considerable numbers of cells with little or no AXL. These cells remained sensitive to the BRAF- and MEK-inhibitors.
Boshuizen therefore proposed to combine BRAF/MEK-inhibitors (to kill the Low-AXL cells) with HuMax-AXL-ADC (to kill the High-AXL cells). Collaboration was then set up between the two organizations to develop a new combination therapy targeting differential tumour cell sensitivities to a drug.
Results
The team shows that the new combination therapy is effective in mice with melanomas that were resistant to the standard treatment. Moreover, they found that BRAF/MEK-inhibitors stimulated the production of AXL in tumour cells, rendering HuMax-AXL-ADC even more effective in a combination treatment.
They suggest that the combination treatment strategy eliminated both the Low-AXL and high-AXL groups of tumour cells, resulting in longer clinical response.
Implication
Important pre-clinical evidence for the efficacy of the new combination strategy based on tumour cell differential sensitivities to a drug has been demonstrated in mice melanoma.
AXL protein is expressed in multiple cancer types and high levels are associated with resistance to many drug therapies and drug combinations. Targeting cancer cells that express this protein can be a beneficial approach to eliminate drug resistant cancer cells.
Genmab is currently testing HuMax-AXL-ADC in patients with a number of different types of tumours, including patients with melanoma, to assess safety, side effects and efficacy.
This research was funded by the Dutch Cancer Society KWF, and the European Research Council, and Genmab A/S.
