Dr. Yadav on the Olaparib/Neratinib Combo in HER2+ Uterine Serous Carcinoma

Ghanshyam Yadav, MD
Published: Tuesday, Sep 10, 2019



Ghanshyam Yadav, MD, resident physician, Baylor College of Medicine, discusses research surrounding the combination of the PARP inhibitor olaparib (Lynparza) and the pan-HER TKI neratinib (Nerlynx), which proved to be highly synergistic and had significant activity in preclinical models of HER2-positive uterine serous carcinoma.

Yadav and his team began to hypothesize about the combination after reading a paper on breast cancer that determined PI3K inhibition also changes the BRCA mutation. Previously, these 2 pathways were thought to look entirely different. Neratinib inhibits the HER/ERBB2 pathway and olaparib inhibits the DNA damage repair pathway; however, Yadav and his team started to hypothesize whether there was a connection between the two pathways, which led to this investigation.

In the study, it was found that once the cell is treated with a PARP inhibitor, HER2 expression increases on the cell surface, providing more targets for neratinib, Yadav explains. Then, when these cells were treated with neratinib, there was an increase in PARP expression, suggesting more DNA damage, says Yadav. When PARP is taken away, more DNA is damaged, which is why the combination is synergistic. When the combination was tested on mice, there was a significantly longer survival and statistically significant differences in tumor growth in one of the cell lines, Yadav concludes.
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Ghanshyam Yadav, MD, resident physician, Baylor College of Medicine, discusses research surrounding the combination of the PARP inhibitor olaparib (Lynparza) and the pan-HER TKI neratinib (Nerlynx), which proved to be highly synergistic and had significant activity in preclinical models of HER2-positive uterine serous carcinoma.

Yadav and his team began to hypothesize about the combination after reading a paper on breast cancer that determined PI3K inhibition also changes the BRCA mutation. Previously, these 2 pathways were thought to look entirely different. Neratinib inhibits the HER/ERBB2 pathway and olaparib inhibits the DNA damage repair pathway; however, Yadav and his team started to hypothesize whether there was a connection between the two pathways, which led to this investigation.

In the study, it was found that once the cell is treated with a PARP inhibitor, HER2 expression increases on the cell surface, providing more targets for neratinib, Yadav explains. Then, when these cells were treated with neratinib, there was an increase in PARP expression, suggesting more DNA damage, says Yadav. When PARP is taken away, more DNA is damaged, which is why the combination is synergistic. When the combination was tested on mice, there was a significantly longer survival and statistically significant differences in tumor growth in one of the cell lines, Yadav concludes.

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