Key Pathways in Cancer and Targeted Treatment

Cancer is often characterized by dysregulation in cellular pathways and the checkpoints which control cell proliferation, growth, differentiation, and apoptosis. Within the genome there are two types of genes which carefully control cell proliferation and cell death, which are often the driving force behind oncogenesis. Proto-oncogenes drive cell cycle progression while tumor suppressor genes act as checkpoints on the cell cycle; mutations or dysregulation in these types of genes are seen across most if not all cancer types.

The most commonly mutated gene in cancer is TP53, a transcription factor ¹ which acts as a tumors suppressor gene. The protein P53 is a critical component of multiple cellular pathways including response to DNA damage ². The intracellular levels of P53 are kept low by ubiquitination, however when a cell is under stress the ubiquitination is inhibited and P53 accumulates in the cell ¹. The accumulation of P53 triggers transcriptional activation of genes associated with apoptosis, acting as a tumor suppressor ¹. In cancer, mutations in TP53 can cause the protein to be expressed in much smaller amounts or not at all. Additionally, mutations can cause P53 to gain additional function or loose the correct function ³. As P53 is involved in DNA damage response ⁴, the lack of functioning P53 means a cell with DNA damage will not undergo apoptosis, resulting in the survival of mutated, potentially cancerous cells. Current treatment strategies involve promoting the activation of functioning P53 and preventing its degradation ⁵, although these are still in trial stages.

Recently, PD-1 and PD-L1 have been at the forefront of cancer research and development, as cancer cells use the PD-1/PD-L1 pathway to escape immune system detection. PD-L1 is normally found in the placenta, lungs and tonsils, tissues that promote immune tolerance ⁶, however, certain cancer types have been shown to express PD-L1 to create immune tolerance to the tumor. Treatment strategies currently being trialed for breast, lung and gastrointestinal cancers that overexpress PD-L1 mainly target the PD-1 receptor present on T-cells by using targeted immunotherapies ⁶. Additionally, there are also trials for antibodies targeting PD-L1 ⁷ on the cancer cells. The over expression of PD-L1 is used to avoid apoptosis signals ⁸, usually initiated by T-cells, and in fact downregulates the immune response to the tumor through apoptosis of immune cells that would otherwise have recognized the tumor ⁹.

In cancer, the lack of differentiation and the accumulation of immature cells can inhibit the normal function of the tissue. In acute promyelocytic leukaemia ^APL the accumulation of immature myeloid cells is caused by a genetic translocation ^t15;17, resulting the production of a fusion protein, PML-RARα ¹⁰. The PML-RARα fusion protein alters the ability of the Retinoic Acid Receptor to function properly, a critical component of stem cell differentiation, resulting in the accumulation of non-functioning cells. When RARα functions properly it prevents transcriptional activation until retinoic acid binds. This then allows a conformational change in the DNA, promoting transcription of genes related to differentiation ¹¹. The current treatment recommendation for APL includes the use of all-trans retinoic acid ^{ATRA 12}, although the mechanism of action is not clearly understood. It is thought that ATRA forces differentiation by inducing the normal function of the RARα protein, or inducing expression of a non-mutated allele ¹³, alternatively, it could promote degradation of the PML-RARα fusion protein ¹¹ by autophagy, reducing the presence of the non-functioning protein making way for normal transcription. The idea of differentiation therapy has been proposed in different cancer types including breast cancer and glioblastoma ¹², with clinical trials underway to target other pathways associated with differentiation.

There are many different cellular pathways which control proliferation, growth, differentiation and apoptosis. Although biologically there are redundancies in these pathways to prevent tumorigenesis and cancer survival, there are critical pathways like PD-1/PD-L1 and P53 that are critical components of normal cellular functions. By establishing reliable cell line models, further strategies to overcome common mutations in cancer can be developed.

This is but a highlight of three key pathways involved in various cancers, but all of these pathways involve a variety of different receptors, effectors, ligands, and other signalling molecules. Our HAP1 and Cancer cell lines include key genes across many different cancer pathways, as assessed by Kegg Pathway Analysis. Check out the table below for your gene of interest.

Gene knockouts available in HAP1 Cell Line
Gene knockouts available in HAP1 and Cancer Cell Lines
Gene knockouts available in Cancer Cell Lines

References

1. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Wang, H., Guo, M., Wei, H. et al. 92, s.l. : Sig Transduct Target Ther, 2023, Vol. 8.
2. An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Wei Xiong, Xiaosong Wu, Sarah Starnes, Sarah K. Johnson, Jeff Haessler, Siqing Wang, Lijuan Chen, Bart Barlogie, John D.
Shaughnessy, Jr, Fenghuang Zhan. 4235–4246, s.l. : Blood, 2008, Vol. 112 (10).
3. p53 mutations in cancer. . Muller, P., Vousden, K. 2013, Nat Cell Biol , Vol. 15.
4. The diversity of p53 mutations among human brain tumors and their functional consequences. Agata Zupanska, Bozena Kaminska,. 7, s.l. : Neurochemistry International,, 2002, Vol. 40.
5. Targeting p53 for the treatment of cancer,. Michael J. Duffy, Naoise C. Synnott, Shane O’Grady, John Crown,. s.l. : Seminars in Cancer Biology,, 2022, Vol. 79.
6. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Hamanishi, J., Mandai, M., Matsumura, N. et al. 462–473, s.l. : Int J Clin Oncol, 2016, Vol. 21.
7. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. Shen X, Zhao B. k3529, s.l. : BMJ, 2018, Vol. 362.
8. Regulation and Function of the PD-L1 Checkpoint. Chong Sun, Riccardo Mezzadra, Ton N. Schumacher. 3, s.l. : Immunity, 2018, Vol. 48.
9. PD-1/PD-L1 pathway: current researches in cancer. Han Y, Liu D, Li L. 3, s.l. : Am J Cancer Res, 2020, Vol. 10.
10. The theory of APL. Piazza, F., Gurrieri, C. & Pandolfi, P. 7216–7222, s.l. : Oncogene, 2001, Vol. 20.
11. All-Trans-Retinoic Acid Combined With Valproic Acid Can Promote Differentiation in Myeloid Leukemia Cells by an Autophagy Dependent Mechanism. Benjamin DN, O'Donovan TR, Laursen KB, et al. 848517, s.l. : Front Oncol., 2022, Vol. 12.
12. Cancer stem cells and differentiation therapy. Jin X, Jin X, Kim H. 10, s.l. : Tumor Biology, 2017, Vol. 39.
13. All-trans-retinoic acid treatment and retinoic acid receptor alpha gene rearrangement in acute promyelocytic leukemia: a model for differentiation therapy. Degos, L. 2, s.l. : nternational journal of cell cloning, 1992, Vol. 10.
14. p53 mutations in cancer. Muller, P., Vousden, K. s.l. : Nat Cell Biol, 2013, Vol. 15.