Pi3K- And Mtor-Dependent Mechanisms Of Lapatinib Resistance And Resulting Therapeutic Opportunities

Author

Samuel Brady, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

8-2014

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dihua Yu

Committee Member

Zhimin Lu

Committee Member

Hui-Kuan Lin

Committee Member

Anil Sood

Committee Member

Pierre McCrea

Abstract

Breast cancers with HER2 amplification represent 20-25% of breast cancer cases and are frequently responsive to the HER2 kinase inhibitor lapatinib, but generally for only short duration. We aimed to understand how breast cancers with HER2 amplification become resistant to lapatinib, in order to identify potential therapies that can overcome lapatinib resistance. To establish lapatinib resistance models we treated three HER2+ breast cancer cell lines with lapatinib for several months until they became lapatinib-resistant. We then compared lapatinib-sensitive (parental) cells with their lapatinib-resistant (LapR) counterparts to identify changes conferring lapatinib resistance. We found that activation of PI3K, specifically the p110α catalytic subunit, was enhanced in two out of three LapR cell lines, through p110α activating mutations and/or upregulation. In a third LapR cell line, mTOR activation was enhanced in a manner independent of its usual PI3K/Akt-mediated activation or other known mTOR activators. Thus, all three cell lines possessed increased activation of the PI3K/mTOR pathway, suggesting the use of PI3K and/or mTOR inhibitors in lapatinib-resistant breast cancers. We found that p110α-specific PI3K inhibition effectively overcame lapatinib resistance in LapR cell lines and xenografts with increased p110α activation, while the LapR cell line with PI3K-independent mTOR activation was sensitive to mTOR inhibition but resistant to PI3K inhibitors. mTOR activation in lapatinib-resistant breast cancer cells was accompanied by increased levels of the inhibitors of apoptosis (IAP) family, which could be reversed by the mTOR kinase inhibitor AZD8055 or the Hsp90 inhibitor 17-AAG. Together these data strongly suggest the use of PI3K/mTOR inhibitors or Hsp90 inhibitors to prevent or delay lapatinib resistance. Further, we found that p110α-specific PI3K inhibition in combination with lapatinib was both effective against LapR xenografts and well-tolerated in mice. Thus pan-PI3K inhibition may not be necessary for some lapatinib-resistant patients, thus sparing them the toxicities of inhibition all four class I PI3K isoforms.

Keywords

Lapatinib, HER2, mTOR, PI3K, BYL719