Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer

Kloth, Michael; Ruesseler, Vanessa; Engel, Christoph; Koenig, Katharina; Peifer, Martin; Mariotti, Erika; Kuenstlinger, Helen; Florin, Alexandra; Rommerscheidt-Fuss, Ursula; Koitzsch, Ulrike; Wodtke, Claudia; Ueckeroth, Frank; Holzapfel, Stefanie; Aretz, Stefan; Propping, Peter; Loeffler, Markus; Merkelbach‐Bruse, Sabine; Odenthal, Margarete; Friedrichs, Nicolaus; Heukamp, Lukas C.; Zander, Thomas; Buettner, Reinhard

doi:10.1136/gutjnl-2014-309026

Cited by 67 publications

(61 citation statements)

References 45 publications

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“…While this paper was under review, Kloth and colleagues published that 15% of Lynch syndrome or Lynch-like CRC have HER2 mutations and they showed that the HER2 mutant CRC cell lines, CW-2 and CCK-81, are sensitive to treatment with neratinib and afatinib (31). Our PDX results suggest that dual HER2 targeted therapy may be needed to achieve optimum anti-tumor effect.…”

Section: Discussionmentioning

confidence: 99%

HER2 Activating Mutations Are Targets for Colorectal Cancer Treatment

et al. 2015

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The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of colorectal cancer patients. Introduction of the HER2 mutations, S310F, L755S, V777L, V842I, and L866M, into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutations are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors, neratinib and afatinib. HER2 gene sequencing of 48 cetuximab resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) WT colorectal cancer patient-derived xenografts (PDX’s) identified 4 PDX’s with HER2 mutations. HER2 targeted therapies were tested on two PDX’s. Treatment with a single HER2 targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2 targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2 mutated PDX’s.

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Section: Discussionmentioning

confidence: 99%

HER2 Activating Mutations Are Targets for Colorectal Cancer Treatment

et al. 2015

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“…Analysis of microsatellite status was performed with the previously described methods. 46 For examination of somatic APC mutations, targeted sequencing with high coverage (read depths > 1000) was performed using the FAP MASTR Kit (Multiplicom) on a MiSeq platform (Illumina) in one person (individual 1661.1). The results were analyzed with the SeqPilot software (JSI Medical Systems).…”

Section: Methodsmentioning

confidence: 99%

“…46 This involved use of the National Cancer Institute (NCI) reference marker panel for the evaluation of microsatellite instability (MSI) in colorectal cancer. This panel consists of two mononucleotide (BAT25, BAT26), and three dinucleotide (D2S123, D5S346 and D17S250) repeats.…”

Section: Methodsmentioning

confidence: 99%

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Adam

Spier

Zhao

et al. 2016

The American Journal of Human Genetics

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In around 30% of families with colorectal adenomatous polyposis, no germline mutation in the previously-implicated genes APC, MUTYH, POLE, POLD1, or NTHL1 can be identified, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis was performed. We identified two unrelated individuals with differing compound-heterozygous loss-of-function germline mutations in the mismatch repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1g>a, c.2760delC, c.3001-2a>c) was indicated on RNA and protein level. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST) and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the loss-of-function effect and causal relevance of the mutations. The pedigrees, genotypes, and the frequency of MSH3 mutations in the general population are consistent with an autosomal recessive mode of inheritance. Both index persons had an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing Constitutional Mismatch Repair Deficiency Syndrome (CMMRD). Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study we describe biallelic germline mutations of MSH3 in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.

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“…More recently, however, ERBB2 mutations at such hotspot loci were reported to be recurrent in MSI CRC. Kloth et al (8) reported that 15% of BRAF wild-type MSI CRC harbor ERBB2 mutations with these tumors harboring highly recurrent L755S and V842I substitutions, as well as new variants L726F, A848T and G865R. In that study, MSI CRC cell lines harboring such ERBB2 mutations were highly sensitive to irreversible EGFR/ERBB2 small molecule tyrosine kinase inhibitors, highlighting their potential role in the treatment of ERBB2 mutated CRC regardless of mismatch repair status.…”

mentioning

confidence: 88%