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The combination of RMC4550 (SHP2 inhibitor) and LY3214996 (ERK inhibitor) effectively impairs tumor growth and induces tumor regression in multiplein vivo models of PDAC

ABSTRACT: The combination of RMC4550 (SHP2 inhibitor) and LY3214996 (ERK inhibitor) effectively impairs tumor growth and induces tumor regression in multiplein vivo models of PDAC

PROVIDER: PRJNA882086 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21628726.fastq.gz	Fastqsanger.gz
	SRR21628727.fastq.gz	Fastqsanger.gz
	SRR21628728.fastq.gz	Fastqsanger.gz
	SRR21628729.fastq.gz	Fastqsanger.gz
	SRR21628730.fastq.gz	Fastqsanger.gz

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Project description:KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime goal. Recently, inhibitors (G12C-Is) that bind KRAS-G12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRAS-G12C activation and inhibitor engagement, we found that SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRAS-G12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. The combination of SHP2-I and G12C-I evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using an inhibitor-resistant SHP2 mutant showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but SHP2-Is also had direct effects on angiogenesis. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies. G12C-Is show significant, but limited, efficacy as single agents, in part because of “adaptive resistance”. We find that combining G12C-Is with SHP2-Is abrogates adaptive resistance and results in favorable changes in the immune microenvironment that potentiate PD-1 blockade in KRAS-mutant malignancies. SHP2-Is also can have direct, context-dependent, effects on tumor vasculature.

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Project description:KRAS mutant pancreatic tumors have poor prognosis and few therapeutic options. Here, Frank et al. show that the combination of RMC4550 (SHP2 inhibitor) and LY3214996 (ERK inhibitor) effectively impairs tumor growth and induces tumor regression in multiplein vivo models of PDAC .

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Project description:The first bona fide PTP proto-oncogene was the Src-homology 2 domain-containing phosphatase SHP2 (encoded by PTPN11), an ubiquitously expressed PTP that transduces mitogenic, pro-survival, cell fate and/or pro-migratory signals from numerous growth factor-, cytokine- and extracellular matrix receptors. In malignancies, SHP2 is hyperactivated either downstream of oncoproteins or by mutations.We provide analysis of a primary triple-negative breast tumor grown as xenografts in the presence or absence of SHP2 for 30 days. A primary triple-negative breast tumor (BT8) was transduced with a doxycycline-inducible lentiviral vector expressing a CTRL miR or SHP2 miR1 or SHP2 miR2. Cells from each group were injected in immunodeficient mice and after tumor development, the knockdown of SHP2 was induced for 30 days in vivo. At day 30, tumors were dissected and RNA isolated for gene expression analysis.

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