Novel Mutations in Neuroendocrine Carcinoma of the Breast

Ang, Daphne; Ballard, Morgan; Beadling, Carol; Warrick, Andrea; Schilling, Amy; O’Gara, Rebecca; Pukay, Marina; Neff, Tanaya; West, Robert B.; Corless, Christopher L.; Troxell, Megan L.

doi:10.1097/pdm.0b013e3182a40fd1

Cited by 56 publications

(44 citation statements)

References 38 publications

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“…FGFR4 has been reported to play a very important role in metastasis, drug resistance, and poor prognosis (23,(68)(69)(70); therefore FIIN-2 and FIIN-3, with good FGFR4 potency, show promising potential for application in many FGFR-dependent cancer types such as breast cancer (63,71) and hepatocellular carcinoma (72,73). In addition, they are capable of overcoming the valine-to-methionine gatekeeper mutation in H2077 and H1581 cell lines, although similar mutations found in patients' specimens have been demonstrated experimentally to confer resistance to the leading clinical FGFR inhibitors (19,48,50).…”

Section: Discussionmentioning

confidence: 99%

“…The FGFR2 V564I gatekeeper mutant was isolated as a resistant clone in a FGFR2 Ba/F3 screen of dovitinib and also was reported to confer resistance to the multitargeted drug ponatinib (19). In humans the FGFR4 V550L gatekeeper mutation was detected in 9% (4/43) of embryonal rhabdomyosarcoma tumors (49), and the FGFR4 V550M mutation was detected in 13% (2/15) of neuroendocrine breast carcinomas (50). To overcome gatekeeper mutations found in primary FGFR-driven cancers and those that likely will arise in FGFR inhibitor-treated tumors in the future, we developed next-generation covalent FGFR inhibitors.…”

Section: Significancementioning

confidence: 99%

“…The H-bond of this pseudo ring was envisioned to provide greater rotatory flexibility to the dichlorodimethoxylphenyl group of FIIN-3, which could better tolerate the methionine gatekeeper. FIIN-3 potently inhibits both WT FGFRs (EC 50 in the 1-to 41-nM range) and the gatekeeper mutant of FGFR2 (EC 50 of 64 nM). Both FIIN-2 and FIIN-3 possess a 4-acrylamidebenzyl group in contrast to the 3-acrylamidebenzyl group in FIIN-1 and maintain the ability to form a covalent bond with the P-loop cysteine but alter the selectivity profile versus other kinases.…”

Section: Significancementioning

confidence: 99%

“…After 72 h the cells were assessed by MTS tetrazolium assay. The IC 50 values were calculated using GraphPad Prism version 5.0 (GraphPad Software Inc.). To generate FGFR2 mutants, V564M, C491A, or C491A/V564M were introduced into Tel-FGFR2 WT cells using site-directed mutagenesis (Agilent) followed by introduction into Ba/F3 cells using retroviral infection.…”

Section: Fgfr2-r: 5′-acgaatggtctagaaagctttcatgttttaacactgccgtttatg-3′mentioning

confidence: 99%

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Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

163

132

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The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Fgfr2-r: 5′-acgaatggtctagaaagctttcatgttttaacactgccgtttatg-3′mentioning

confidence: 99%

See 2 more Smart Citations

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

163

132

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“…In a recent study, primary or metastatic NECB were screened for mutations in common cancer genes [49]. Mutations were found in 5 of 15 tumors.…”

Section: Future Perspectivesmentioning

confidence: 99%

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

et al. 2015

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Neuroendocrine carcinoma of the breast is considered a rare entity, and for this reason there are no data from prospective clinical trials on its optimal management. Early stage tumors are usually treated with the same strategy used for the other types of invasive breast cancer. Anthracycline-and taxane-based regimens represent the most frequently administered chemotherapy in neoadjuvant and adjuvant setting, as well as for metastatic disease, although combinations of platinum compounds and etoposide have been widely used, in particular for small-cell histology and tumors with a high proliferation index. For metastatic disease, a multimodality therapeutic strategy can be considered on an individual basis, with chemotherapy, endocrine therapy, peptide receptor radionuclide therapy, radiation therapy, surgery, or a combination of the above. In the near future, a better knowledge of the biology of these tumors will hopefully provide new therapeutic targets for personalized treatment. In this review, we discuss the current evidence and the future perspectives on diagnosis and treatment of neuroendocrine carcinoma of the breast. The Oncologist 2016;21:28-32 Implications for Practice: Neuroendocrine carcinoma of the breast (NECB) is a distinct entity of breast cancer. Clinical features and morphology are not helpful to distinguish NECB from other subtypes of breast cancer; therefore, immunohistochemistry markers for neuroendocrine differentiation, mainly chromogranin and synaptophysin, should be routinely used to confirm the diagnosis, especially in cases of mucinous or solid papillary carcinoma in which the suspicion of NECB may be relevant. Adjuvant treatment should be offered according to the same recommendations given for the other types of invasive breast cancer. An accurate diagnosis of NECB is also important in the metastatic setting, in which a multimodality approach including specific therapies such as peptide receptor radionuclide therapy can be considered.

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The genetic landscape of breast carcinomas with neuroendocrine differentiation

Marchiò

Geyer

et al. 2016

J. Pathol.

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Neuroendocrine breast carcinomas (NBCs) account for 2–5% of all invasive breast cancers and are histologically similar to neuroendocrine tumours from other sites. They typically express oestrogen receptor (ER), are HER2-negative and of luminal 'intrinsic' subtype. Here we sought to define the mutational profile of NBCs, and to investigate whether NBCs and common forms of luminal (ER+/HER2-) breast cancer display distinct repertoires of somatic mutations. Eighteen ER+/HER2- NBCs, defined as harbouring >50% of tumour cells expressing chromogranin A and/or synaptophysin, and matched normal tissue were microdissected and subjected to massively parallel sequencing targeting all exons of 254 genes most frequently mutated in breast cancer and/or related to DNA repair. Their mutational repertoire was compared to that of ER+/HER2- (n=240), PAM50-defined luminal breast cancers (n=209 luminal A; n=111 luminal B) and invasive lobular carcinomas (n=127) from The Cancer Genome Atlas. NBCs were found to harbour a median of 4.5 (range 1-11) somatic mutations, similar to that of luminal B breast cancers (median=3, range 0-17) but significantly higher than that of luminal A breast cancers (median=3, range 0-18, p=0.02). The most frequently mutated genes were GATA3, FOXA1, TBX3, ARID1A (3/18, 17%), and PIK3CA, AKT1, CDH1 (2/18, 11%). NBCs less frequently harboured PIK3CA mutations than common forms of ER+/HER2, luminal A and invasive lobular carcinomas (p<0.05) and displayed a significantly higher frequency of somatic mutations affecting ARID1A (17% versus 2%, p<0.05) and the transcription factors FOXA1 (17% versus 2%, p=0.01) and TBX3 (17% versus 3%, p<0.05) than common-type ER+/HER2- breast cancers. No TP53 somatic mutations were detected in NBCs. Compared to common forms of luminal breast cancers, NBCs display a distinctive repertoire of somatic mutations featuring lower frequency of TP53 and PIK3CA mutations, and enrichment for FOXA1, TBX3 mutations, and akin to neuroendocrine tumours from other sites, ARID1A mutations.

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Novel Mutations in Neuroendocrine Carcinoma of the Breast

Cited by 56 publications

References 38 publications

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

The genetic landscape of breast carcinomas with neuroendocrine differentiation

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