Identifying mechanisms of resistance to PI3K inhibition in head and neck squamous cell carcinoma
Seung June Kim, MSc.
August 30, 2021
Targeted cancer therapy uses specific drugs that interfere with pathways involved in cancer progression. Such pathways should be under strict control, but cancer cells often find ways to evade it, and grow without prompt. In head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, one of the most frequently broken pathways is called the PI3K pathway (Lawrence et al., 2015). Under normal conditions, the P13K pathway regulates various cellular processes, but mutations in the protein, PI3K, render it over-active, promoting tumour growth and progression (Engelman, 2009).
Alpelisib is a specific drug that can inhibit the P13K pathway. However, some patients are developing resistance. After a drug has been bombarding cancer cells, the cancer cells can learn a way to develop around it, survive the treatment and keep growing. Understanding how and why cancer cells developed resistance to alpelisib is important to its application in HNSCC. Hence, in 2020 a group of researchers in the Translational Head and Neck Cancer Research Program at the London Regional Cancer Program sought to uncover how HNSCC cells become resistant to alpelisib (Ruicci et al., 2020).
To mimic drug resistance in patients, the researchers treated HNSCC cells with a moderate dose of alpelisib and waited until the cells became resistant. A very high dose would obliterate all cancer cells and no resistant cells will emerge. However, a moderate dose would not kill every cell and apply enough pressure that a subset of the cells would overcome the effects of alpelisib and become resistant. When the cells became resistant, a higher amount of the drug was necessary to kill those cells than that of the original cells. Which lines up with what happens in patient treatments: eventually the same dose no longer has the same effect as the tumour develops resistance. The original and resistant cell populations enabled the researchers to look for proteins specifically more abundant in the resistant cells. The researchers believed these proteins might be enabling the cancer cells to become resistant to the drug.
After analyzing hundreds of proteins they identified two proteins called TYRO3 and AXL as more abundant in the drug-resistant group compared to the original cells. This is the first time TYRO3 has been implicated in driving resistance to alpelisib. To verify that TYRO3 and AXL were key players in developing resistance, the researchers selectively removed the two proteins in HNSCC cells and exposed them to alpelisib. The cells response to alpelisib effectively demonstrated that the that TYRO3 and AXL proteins make the cells resistant to alpelisib. Furthermore, similar findings were observed in patient-derived xenografts (PDXs), where patient tumour samples are implanted into a model animal for research (usually mice in basic science research). There are two main advantages to this type of experiment. 1) PDX models use freshly obtained cancer cells from patients, so they likely better representation “real-life” cancer than established cancer cells. Since established cancer cells have been growing and dividing under laboratory conditions over the course of many years after they were first sampled and may have changed from the original. 2) A xenograft model provides a better and more realistic approximation of cancer cell growth in “real-life” compared to cancer cells grown in a plastic dish. In their PDX experiment, the researchers observed higher levels of TYRO3 in multiple alpelisib-resistant PDXs compared to untreated samples, supporting the findings of the earlier HNSCC cell experiments.
Ultimately, these findings suggest that TYRO3 and AXL proteins are key players that can drive resistance to alpelisib in HNSCC. Knowing this information allows researchers to explore how to better combat alpelisib resistance in HNSCC treatments. Possibly by introducing a drug that targets TYRO3 and AXL proteins in hopes of delaying or stopping resistance to alpelisib. Further research is needed to understand how cancer resistance can be effectively overcome in patients, however identifying the key proteins involved is a great stepping stone.
(Ruicci et al. is the main article)
Engelman, J. A. (2009). Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nature Reviews. Cancer, 9(8), 550–562. https://doi.org/10.1038/nrc2664
Lawrence, M. S., Sougnez, C., Lichtenstein, L., Cibulskis, K., Lander, E., Gabriel, S. B., Getz, G., Ally, A., Balasundaram, M., Birol, I., Bowlby, R., Brooks, D., Butterfield, Y. S. N., Carlsen, R., Cheng, D., Chu, A., Dhalla, N., Guin, R., Holt, R. A., … International Genomics Consortium. (2015). Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, 517(7536), 576–582. https://doi.org/10.1038/nature14129
Ruicci, K. M., Meens, J., Plantinga, P., Stecho, W., Pinto, N., Yoo, J., Fung, K., MacNeil, D., Mymryk, J. S., Barrett, J. W., Howlett, C. J., Boutros, P. C., Ailles, L., & Nichols, A. C. (2020). TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma. Journal of Experimental & Clinical Cancer Research, 39(1), 217. https://doi.org/10.1186/s13046-020-01713-9