Differences in sensitivity to EGFR inhibitors could be explained by described biochemical differences between oncogenic Ras mutants

Abstract

Emerging data suggest different activating Ras mutants may have different biological behaviors. The most striking example may be in colon cancer, where activating KRAS mutations generally indicate a lack of benefit to treatment with EGFR inhibitors, although the activating KRAS G13D mutation appears to be an exception. As KRAS G13D generally shares the same biochemical defects as the other oncogenic KRAS mutants, a mechanism for differential sensitivity is not apparent. Here, a previously developed mathematical model of Ras mutant signaling is used to investigate this problem. The purpose of the analysis is to determine whether differential response is consistent with known mechanisms of Ras signaling, and to determine if any known features of Ras mutants provide an explanation for differential sensitivity. Computational analysis of the mathematical model finds that differential response to upstream inhibition between cancers with different Ras mutants is indeed consistent with known mechanisms of Ras biology. Moreover, model analysis demonstrates that the subtle biochemical differences between G13D and G12D (and G12V) mutants are sufficient to enable differential response to upstream inhibition. Simulations suggest that wild-type Ras within the G13D mutant context is more effectively inhibited by upstream inhibitors than when it is in the G12D or G12V contexts. This difference is a consequence of an elevated Km for the G13D mutant. The identification of a single parameter that influences sensitivity is significant in that it suggests an approach to evaluate other, less common, Ras mutations for their anticipated response to upstream inhibition.

A quantitative systems pharmacology analysis of KRAS G12C covalent inhibitors

“…Of note, oncogenic mutants at codon 12, 13, and 61 are biochemically similar [23]. However, there are subtle differences between different oncogenic mutants that, in some cases, can have large effects [11,24]. For that reason, we extended the model to include G12C by incorporating recently published data [25].…”

Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

“…We also have revealed that the sensitivity of KRAS G12C cells to the EGFR inhibitor cetuximab has a similar mechanism as what we recently demonstrated for KRAS G13D and its response to cetuximab (14). For the KRAS G13D study, we first used mathematic modeling of available biochemical detect to predict a priori that reductions in wild-type RAS explained the response of KRAS G13D CRC to EGFR inhibition (17). In contrast, for this study we first identified KRAS G12C CRC as a genotype that was sensitive to EGFR inhibition empirically, and then we used our mathematical model to evaluate whether the observed deficiencies in the binding of KRAS G12C to NF1 and CRAF, as well as the dependency on the number of KRAS alleles mutated, were consistent with the known mechanisms of RAS signal regulation.…”

“…Our previous finding that EGFR inhibitors like cetuximab can reduce WT HRAS-GTP and NRAS-GTP in KRAS G13D CRC cells was first uncovered by our mathematical modeling (17). Our mathematical model of oncogenic RAS signaling was developed to be capable of modeling specific RAS mutant alleles on the basis of their kinetic, equilibrium, and enzymatic biochemical parameters for the reactions that regulate RAS-GTP cycling (18)(19)(20).…”

A computational panel of pathological RAS mutants with implications for personalized medicine and genetic medicine

“…We have previously used modeling to address specific questions pertaining to RAS mutants G12D, G12V, F28L, G12C, and G13D [8,15]. Here, an extension of the number of mutants studied was undertaken to develop intuition for how a collection of related, but distinct, pathological mutants might behave.…”

“…Our original RAS model focused on the oncogenic G12D and G12V mutants, as well as fast-cycling F28L mutant [8]. To study problems pertaining to specific RAS mutants important to cancer, we have since extended our model to include G13D, Q61L, Q61K, Q61W, Q61H, Q61P, and Q61R [15] and G12C. We here extend our model to an additional 6 oncogenic mutations: G12R, G12P, G13S, G13V, A59T, and 10dupG, yielding a total of 16 different oncogenic mutants We considered the case where all of the RAS in the cell is mutated (Figure 3A,B).…”