Format

Send to

Choose Destination
Cell Mol Bioeng. 2018;11(6):451-469. doi: 10.1007/s12195-018-0542-y. Epub 2018 Jul 26.

Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition.

Author information

1
1Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA.
2
2Department of Bioengineering, Jonsson Comprehensive Cancer Center, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095 USA.

Abstract

Introduction:

Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed.

Methods:

To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model.

Results:

We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming.

Conclusions:

Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development.

KEYWORDS:

Axl; BET inhibition; EGFR; Erk inhibition; Her2; Mek inhibition; Met; Triple negative breast cancer

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center