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Cellular States Dictate Adaptive Signaling Responses to KRASG12C Inhibition: Drug Response pY Profiling

ABSTRACT: Covalent inhibitors of KRASG12C (KRASi) hold considerable progress for tumors driven by this oncogene yet early studies suggest rapid mechanisms of adaptive resistance that appear cell type dependent. To address these challenges, we performed mass spsectrometry baesd phosphoproteomics analysis in KRASG12C cell lines after short term treatment with ARS-1620 and compared phosphoproteomes of KRASG12C cells to understand signaling diversity. Our analysis suggests individual KRASG12C cells responds uniquely to perturbation of KRASG12C. Cell line models can be categorized in epithelial or mesenchymal subtypes and a similar pattern was observed in KRASG12C human lung cancer tumor tissues. ERBB2/3 signaling compensate for repressed ERK signaling following ARS-1620 treatment in epithelial cell type, and this subtype was also more responsive to inhibition of SHP2, IGFR, and SOS1. Conversely, FGFR signaling drives resistance to KRASi in mesenchymal cells in part via mTOR signaling. These studies suggest transcriptional subtypes of KRASG12C dictate responsiveness to specific combinations.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Type Ii Pneumocyte

DISEASE(S): Lung Adenocarcinoma

SUBMITTER: John Koomen

LAB HEAD: Eric Haura, MD

PROVIDER: PXD021607 | Pride | 2021-02-15

REPOSITORIES: Pride

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			Action	DRS
	20191107_Haura_KRAS-G12C_TMT-Batch1-pY_run1.raw	Raw
	20191107_Haura_KRAS-G12C_TMT-Batch1-pY_run1.rawF008562.mzid.gz	Mzid
	20191107_Haura_KRAS-G12C_TMT-Batch1-pY_run1.rawF008562.mzid_20191107_Haura_KRAS-G12C_TMT-Batch1-pY_run1.raw_F008562.MGF	Mzid
	20191107_Haura_KRAS-G12C_TMT-Batch1-pY_run1.raw_F008562.dta	Raw
	20191107_Haura_KRAS-G12C_TMT-Batch1-pY_run2.raw	Raw

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