Dataset Information

The temporal effect of RMC-7977 treatment on the PANC-1 cell total proteome

ABSTRACT: KRAS-driven pancreatic ductal adenocarcinoma (PDAC) is dependent on nutrient scavenging pathways to fuel the metabolic demands of proliferation. While acute KRAS loss results in downregulated macropinocytosis, we observed that this downregulation is transient and returns to basal levels in the absence of KRAS. Furthermore, we found that prolonged (7 d) pharmacological inhibition of RAS, KRAS, or MEK resulted in significant upregulation of macropinocytosis. Additionally, we demonstrated that PDAC cells with acquired resistance to RAS inhibitors exhibit a 2- to 10-fold increase in macropinocytosis. Our data suggest We hypothesize that upregulated macropinocytosis may mediate resistance to inhibitors of the RAS ERK-MAPK pathway.  We found that upregulated macropinocytosis in RAS inhibitor-resistant models is accompanied by increased albumin uptake and sensitivity to albumin-bound paclitaxel (nab-paclitaxel). Mechanistically, RAS-inhibitor resistant models exhibit heterogeneous signaling that culminates in increased levels of RAC-GTP, a known driver of macropinocytosis. We conclude that RAS inhibitor-resistant PDAC models upregulate macropinocytosis, which may be exploited for improved delivery of albumin-bound chemotherapeutics.  Within this study, we aimed to evaluate the effects of the pan-RAS inhibitor RMC-7977 on the global proteome of PANC-1 cells. We evaluated the effect at a short-term (24 hour), intermediate (168 hour), and resistant (RASi-R) time points using a global mass spectrometry-based approach.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Duct

SUBMITTER: Scott Lyons

LAB HEAD: Kirsten L Bryant

PROVIDER: PXD066616 | Pride | 2026-06-25

REPOSITORIES: pride

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			Action	DRS
	20250227_Astral_IO_25cm_PC1415_Bryant_DIA_1.raw	Raw
	20250227_Astral_IO_25cm_PC1415_Bryant_DIA_10.raw	Raw
	20250227_Astral_IO_25cm_PC1415_Bryant_DIA_11.raw	Raw
	20250227_Astral_IO_25cm_PC1415_Bryant_DIA_12.raw	Raw
	20250227_Astral_IO_25cm_PC1415_Bryant_DIA_2.raw	Raw

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Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental Lu65 cells to those with acquired resistance to the KRAS G12C inhibitor, Sotorasib. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.

Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental H358 cells to those with acquired resistance to the KRAS G12C inhibitor, AMG510. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.

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The temporal effect of RMC-7977 treatment on the PANC-1 cell total proteome

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