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Cellular States Dictate Adaptive Signaling Responses to KRASG12C Inhibition: Protein Expression

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: PXD021603 | Pride | 2021-02-15

REPOSITORIES: Pride

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			Action	DRS
	20200214_Haura_Hiten_KRAS_8cell_TMT10_ID_Fx01.raw	Raw
	20200214_Haura_Hiten_KRAS_8cell_TMT10_ID_Fx01.rawF008467.mzid.gz	Mzid
	20200214_Haura_Hiten_KRAS_8cell_TMT10_ID_Fx01.rawF008467.mzid_20200214_Haura_Hiten_KRAS_8cell_TMT10_ID_Fx01.raw_F008467.MGF	Mzid
	20200214_Haura_Hiten_KRAS_8cell_TMT10_ID_Fx01.raw_F008467.dta	Raw
	20200214_Haura_Hiten_KRAS_8cell_TMT10_ID_Fx02.raw	Raw

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Project description: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.

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