Defining and targeting adaptations to oncogenic KRAS^G12Cinhibition using quantitative temporal proteomics

Abstract

Covalent inhibitors of the KRAS G12C oncoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and likely to limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and to predict drug combinations that circumvent resistance, we used a mass spectrometry-based quantitative temporal proteomics and bioinformatics workflow to profile the temporal proteomic response to KRAS G12C inhibition in pancreatic and lung cancer 2D and 3D cellular models. We quantified 10,805 proteins across our datasets, representing the most comprehensive KRASi proteomics effort to date. Our data reveal common mechanisms of acute and long-term response between KRAS G12C -driven tumors. To facilitate discovery in the cancer biology community, we generated an interactive 'KRASi proteome' website (https://manciaslab.shinyapps.io/KRASi/). Based on these proteomic data, we identified potent combinations of KRASi with PI3K, HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using our quantitative temporal proteomics-bioinformatics platform, we have comprehensively characterized the proteomic adaptations to KRASi and identified combinatorial regimens to induce cytotoxicity with potential therapeutic utility.

Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

“…While the intracellular signaling events modulated by KRAS are currently being evaluated as potential therapeutic targets 14,15 , much less is known about its potential impact on the cell surface. Elucidating how oncogenic KRAS modifies the cell surface proteome (surfaceome) may improve our understanding of its complex mechanism of action, and possibly identify new attractive therapeutic targets.…”

Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

“…Several recent studies have demonstrated that proteomic profiling of oncogene-induced tumorigenesis can aid the design of new treatment strategies, [41][42][43] and two therapeutic hypotheses are raised by our data. The first is that targeting pathways which demonstrate a compensatory upregulation upon FH inactivation (either at the level of protein abundance or cysteine reactivity) may serve to limit adaptation of cancer cells and trigger cell death.…”

Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

“…Several recent studies have demonstrated that proteomic profiling of oncogene-induced tumorigenesis can aid the design of new treatment strategies, [38][39][40] and two therapeutic hypotheses are raised by our data. The first is that targeting pathways which demonstrate a compensatory upregulation upon FH inactivation (either at the level of protein abundance or cysteine reactivity) may serve to limit adaptation of cancer cells and trigger cell death.…”