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Hypersensitivity of BRCA-Deficient and PALB2-Deficient Cancers

During our lives, our DNA gets damaged from sources such as background radiation. Our bodies have complex systems in place to repair that damage.


Most people have at least two copies of the BRCA1 gene, BRCA2 gene, and PALB2 gene. These are genes that encode proteins that are involved in accurately repairing damage to DNA through a process called homologous recombination. When we have at least one functional copy of each of these genes, our body makes enough of the proteins needed to accurately repair DNA damage.


Some people are born with an inherited BRCA1, BRCA2, or PALB2 mutation that prevents one of the copies of the BRCA1, BRCA2, or PALB2 gene from encoding a functional protein. People with a single inherited mutation do, however, still have a functional second copy of the gene and can accurately repair damage to their DNA.


Sometimes, however, that one functional copy can be lost. When that happens, the cell can no longer accurately repair DNA damage caused by mutations. If the cell mutates in a way that would make it cancerous, the cell cannot accurately repair that damage and the cell can remain cancerous. If the cell then divides, it can create more cancer cells.


Ironically, the very cause of such cancers (the inability to accurately repair DNA damage) can also make them more susceptible to certain drugs. Because the cancer cells cannot accurately repair DNA damage, a chemotherapy drug that damages cancer cell DNA can have profound effects on the ability of the cancer cell to survive.


Drug resistance occurs, however, if a cancer cell develops a reversion mutation that restores the functionality of the defective BRCA1, BRCA2, or PALB2 gene. For this reason, for a drug combination to have a high cure rate in patients with an inherited BRCA1, BRCA2, or PALB2 mutation, it must be able to also kill subpopulations of cancer cells that have restored their ability to accurately repair DNA damage.


General Oncology’s investigational treatment being studied in the SHARON trial is designed to kill the cancer cells that have lost their ability to accurately repair DNA damage as well as those with a restored ability to repair DNA damage.



Sometimes our DNA mutates (gets damaged). Cells can fix the damage (by undoing the mutation). However, to make accurate repairs, the cell needs a functional (non-defective) BRCA1 gene, BRCA2 gene, and PALB2 gene.




People generally have 46 chromosomes. People also generally have two copies each of BRCA1, BRCA2, and PALB2. This example shows the location of the two copies of BRCA1.



People with an inherited BRCA1 mutation have 1 normal copy of the gene and one defective (mutated) copy of the gene. In this picture, green represents the normal gene and red represents the defective gene.




During life, our DNA can mutate. Usually our cells can repair those mutations. In this image, however, the mutation happen to the one functional BRCA1 gene. Without a functional BRCA1 gene, this cell can no longer accurately repair DNA damage.




Without a functional BRCA1 gene, mutations will start to build up over time. Eventually these mutations can make the cell cancerous.




Just like a functional BRCA1, BRCA2, and PALB2 gene are required to accurately repair DNA mutations, a functional copy of BRCA1, BRCA2, and PALB2 are required to accurately repair a different type of damage called a DNA crosslink (a damage caused by certain cancer drugs such as melphalan). Because of this, cancer cells that lack a functional BRCA1, BRCA2, or PALB2 mutation can be hypersensitive to cancer drugs that crosslink DNA.




One way a cancer cell can develop drug resistance (to DNA-damaging drugs) is by a reversion mutation. A reversion mutation is a mutation to DNA that causes the defective gene to be functional again. In this image, the green represents a BRCA1 gene with a reversion mutation. This cancer cell would be able to accurately repair DNA and would be resistant to DNA-damaging drugs.

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