Suppression of mutant Kirsten-RAS (KRASG12D)-driven pancreatic carcinogenesis by dual-specificity MAP kinase phosphatases 5 and 6

Oncogene

2022 Apr 13

Kidger, AM;Saville, MK;Rushworth, LK;Davidson, J;Stellzig, J;Ono, M;Kuebelsbeck, LA;Janssen, KP;Holzmann, B;Morton, JP;Sansom, OJ;Caunt, CJ;Keyse, SM;
PMID: 35418690 | DOI: 10.1038/s41388-022-02302-0

The cytoplasmic phosphatase DUSP6 and its nuclear counterpart DUSP5 are negative regulators of RAS/ERK signalling. Here we use deletion of either Dusp5 or Dusp6 to explore the roles of these phosphatases in a murine model of KRASG12D-driven pancreatic cancer. By 56-days, loss of either DUSP5 or DUSP6 causes a significant increase in KRASG12D-driven pancreatic hyperplasia. This is accompanied by increased pancreatic acinar to ductal metaplasia (ADM) and the development of pre-neoplastic pancreatic intraepithelial neoplasia (PanINs). In contrast, by 100-days, pancreatic hyperplasia is reversed with significant atrophy of pancreatic tissue and weight loss observed in animals lacking either DUSP5 or DUSP6. On further ageing, Dusp6-/- mice display accelerated development of metastatic pancreatic ductal adenocarcinoma (PDAC), while in Dusp5-/- animals, although PDAC development is increased this process is attenuated by atrophy of pancreatic acinar tissue and severe weight loss in some animals before cancer could progress. Our data suggest that despite a common target in the ERK MAP kinase, DUSP5 and DUSP6 play partially non-redundant roles in suppressing oncogenic KRASG12D signalling, thus retarding both tumour initiation and progression. Our data suggest that loss of either DUSP5 or DUSP6, as observed in certain human tumours, including the pancreas, could promote carcinogenesis.

Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling

Nature cancer

2022 Jul 01

Wilding, B;Scharn, D;Böse, D;Baum, A;Santoro, V;Chetta, P;Schnitzer, R;Botesteanu, DA;Reiser, C;Kornigg, S;Knesl, P;Hörmann, A;Köferle, A;Corcokovic, M;Lieb, S;Scholz, G;Bruchhaus, J;Spina, M;Balla, J;Peric-Simov, B;Zimmer, J;Mitzner, S;Fett, TN;Beran, A;Lamarre, L;Gerstberger, T;Gerlach, D;Bauer, M;Bergner, A;Schlattl, A;Bader, G;Treu, M;Engelhardt, H;Zahn, S;Fuchs, JE;Zuber, J;Ettmayer, P;Pearson, M;Petronczki, M;Kraut, N;McConnell, DB;Solca, F;Neumüller, RA;
PMID: 35883003 | DOI: 10.1038/s43018-022-00412-y

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling. Our results suggest that HER2 exon 20 insertion-driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing WT EGFR, paving the way for clinical translation.

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Nature communications

2021 Jun 08

Leach, JDG;Vlahov, N;Tsantoulis, P;Ridgway, RA;Flanagan, DJ;Gilroy, K;Sphyris, N;Vázquez, EG;Vincent, DF;Faller, WJ;Hodder, MC;Raven, A;Fey, S;Najumudeen, AK;Strathdee, D;Nixon, C;Hughes, M;Clark, W;Shaw, R;S:CORT consortium, ;van Hooff, SR;Huels, DJ;Medema, JP;Barry, ST;Frame, MC;Unciti-Broceta, A;Leedham, SJ;Inman, GJ;Jackstadt, R;Thompson, BJ;Campbell, AD;Tejpar, S;Sansom, OJ;
PMID: 34103493 | DOI: 10.1038/s41467-021-23717-5

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.

Oncogenic Kras G12D specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8 + T cells dependent manner

bioRxiv : the preprint server for biology

2023 Feb 18

Mahadevan, KK;McAndrews, KM;LeBleu, VS;Yang, S;Lyu, H;Li, B;Sockwell, AM;Kirtley, ML;Morse, SJ;Moreno Diaz, BA;Kim, MP;Feng, N;Lopez, AM;Guerrero, PA;Sugimoto, H;Arian, KA;Ying, H;Barekatain, Y;Kelly, PJ;Maitra, A;Heffernan, TP;Kalluri, R;
PMID: 36824971 | DOI: 10.1101/2023.02.15.528757

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the KRAS G12D mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the Kras G12D mutant protein. Here we explore the impact of Kras G12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8 + T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8 + T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.

A Phase I, Multicenter, Dose-Escalation Study of the Oral Selective FGFR inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations.

Clin Cancer Res.

2019 Feb 11

Voss MH, Hierro C, Heist RS, Cleary JM, Meric-Bernstam F, Tabernero J, Janku F, Gandhi L, Iafrate AJ, Borger DR, Ishii N, Hu Y, Kirpicheva Y, Nicolas-Metral V, Pokorska-Bocci A, Vaslin Chessex A, Zanna C, Flaherty KT, Baselga J.
PMID: 30745300 | DOI: 10.1158/1078-0432.CCR-18-1959

Abstract

PURPOSE:

To investigate tolerability, efficacy, and pharmacokinetics/-dynamics (PK/PD) of Debio 1347, a selective fibroblast growth factor receptor (FGFR) Inhibitor.

EXPERIMENTAL DESIGN:

This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first 4 weeks on treatment, PK/PD post-first dose and after 4 weeks.

RESULTS:

Seventy-one patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had 6 DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, stomatitis). The maximum tolerated dose was not reached, but dermatological toxicity became sometimes dose-limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, three with FGFR fusions, demonstrated partial responses, 10 additional patients tumor size regressions of ≤30%. Plasma half-life was 11.5 h. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.

CONCLUSIONS:

Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.

Combined KRAS G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS G12C-driven cancers by addressing intrinsic and acquired resistance

bioRxiv : the preprint server for biology

2023 Jan 23

Thatikonda, V;Lu, H;Jurado, S;Kostyrko, K;Bristow, CA;Bosch, K;Feng, N;Gao, S;Gerlach, D;Gmachl, M;Lieb, S;Jeschko, A;Machado, AA;Marszalek, ED;Mahendra, M;Jaeger, PA;Sorokin, A;Strauss, S;Trapani, F;Kopetz, S;Vellano, CP;Petronczki, M;Kraut, N;Heffernan, TP;Marszalek, JR;Pearson, M;Waizenegger, I;Hofmann, MH;
PMID: 36747713 | DOI: 10.1101/2023.01.23.525210

Efforts to improve the anti-tumor response to KRAS G12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRAS G12C inhibitor (KRAS G12C i) to those induced by KRAS G12C i alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRAS G12C i induces an anti-tumor response stronger than that observed with KRAS G12C i alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRAS G12C i treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRAS G12C i-resistant CRC models. Our findings position KRAS G12C plus SOS1 inhibition therapy as a promising strategy for treating both KRAS G12C -mutated tumors as well as for addressing acquired resistance to KRAS G12C i.

Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Cell stem cell

2022 Aug 04

Vasquez, EG;Nasreddin, N;Valbuena, GN;Mulholland, EJ;Belnoue-Davis, HL;Eggington, HR;Schenck, RO;Wouters, VM;Wirapati, P;Gilroy, K;Lannagan, TRM;Flanagan, DJ;Najumudeen, AK;Omwenga, S;McCorry, AMB;Easton, A;Koelzer, VH;East, JE;Morton, D;Trusolino, L;Maughan, T;Campbell, AD;Loughrey, MB;Dunne, PD;Tsantoulis, P;Huels, DJ;Tejpar, S;Sansom, OJ;Leedham, SJ;
PMID: 35931031 | DOI: 10.1016/j.stem.2022.07.008

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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