Abstract 148: A dual and selective small molecule inhibitor of EGFR and PI3 kinase shows promising preclinical activity against KRAS and BRAF mutant colorectal tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.148-148
• Main Authors: Maust, Joel D., Ziemke, Elizabeth K., Frankowski-McGregor, Christy L., Ku, Jun Beom, Mumby, Rachel, Hardiman, Karin M., Whitehead, Christopher E., Sebolt-Leopold, Judith S.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-148

Agents targeting epidermal growth factor receptor (EGFR) have met with limited success in the clinical management of colorectal cancer (CRC). Mutations in KRAS, BRAF, and PIK3CA are important drivers of resistance to EGFR-targeted therapy. Conversely, EGFR-mediated feedback mechanisms serve to mediate resistance to MEK inhibitor-based treatment of CRC by reactivating MAP kinase signaling. Our central hypothesis is that a dual small molecule inhibitor that potently and selectively targets only EGFR and PI3KA, when combined with a MEK inhibitor, will be highly efficacious against subpopulations of BRAF mutant or KRAS mutant colorectal cancers that are dependent upon these kinase molecules to drive tumor progression. Employing a computational modeling approach, we exploited the known binding modes of structurally related ATP binding site inhibitors of EGFR and PI3K to design small molecules that simultaneously inhibit both kinases in a selective manner. To the best of our knowledge, the lead compound MTX-211, whose binding mode is flipped in PI3K compared to EGFR, represents a first in class selective inhibitor of these two critical oncogenic kinases. MTX-211 exhibits a favorable pharmaceutical and selectivity profile, possessing sub- to low nanomolar potency against both targets, >70% oral bioavailability, strong pharmacodynamic modulation of both EGFR and PI3K signaling, and strong in vivo single agent efficacy against multiple BRAFmt and KRASmt colorectal cancer models, as evidenced by T/C values of 29 to 36% after 10-14 days of oral dosing of 50 mg/kg. A significantly higher degree of in vivo activity is seen when MTX-211 is co-administered with the MEK inhibitor trametinib (>400% increase in survival compared to single agent arms), lending support for this polypharmacology approach over triple drug combination strategies. Based on its promising therapeutic profile, MTX-211 is the focus of an ongoing mouse trial of a large panel of patient-derived xenograft BRAFmt and KRASmt CRC models to inform the design of future human clinical trials. Citation Format: Joel D. Maust, Elizabeth K. Ziemke, Christy L. Frankowski-McGregor, Jun Beom Ku, Rachel Mumby, Karin M. Hardiman, Christopher E. Whitehead, Judith S. Sebolt-Leopold. A dual and selective small molecule inhibitor of EGFR and PI3 kinase shows promising preclinical activity against KRAS and BRAF mutant colorectal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeti