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

Abstract

IntroductionTargeted 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.MethodsTo parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1007/s12195-018-0542-y) contains supplementary material, which is available to authorized users.

A census of pathway maps in cancer systems biology

“…Mechanistic models of cancer signalling have been extensively used to study complex phenomena such as feedback loops 60 , crosstalk between pathways [61][62][63][64][65] , oncogene addiction 66 and response to therapy [67][68][69][70][71] . For example, Shin et al 60 showed that the influence of ERK and WNT signalling pathways on epithelial-mesenchymal transition is greatly affected by multiple positive feedback loops.…”

Sporadic ERK pulses drive non-genetic resistance in drug-adapted BRAFV600Emelanoma cells

“…Absolute receptor abundances for EGFR, Her2, Her3 and c-Met were quantified using a Luminex beadbased ELISA procedure as previously described (Claas et al, 2018). A375 cells were cultured in the presence or absence of vemurafenib (1 μM) for 24 hr and then one of four growth factors (EGF, NRG1, FGF8 and HGF at 100 ng/mL) was added for 24 hr.…”

AXL as a Target in Breast Cancer Therapy

“…A systems modeling approach identified decreased AXL expression following MEK inhibition in TNBC cells [53]. AXL expression has been shown to correlate with that of the estrogen (ER) and progesterone (PR) receptors in breast cancer, indicating that estrogen and/or progesterone could regulate AXL expression [54,55].…”