Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy Santarpia, Libero; Lippman, Scott M; El-Naggar, Adel K
Expert opinion on therapeutic targets,
2012-January, 1/1/2012, 2012-Jan, 2012-01-00, 20120101, Letnik:
16, Številka:
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Journal Article
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Introduction:
The MAPK pathway comprises several key signaling components and phosphorylation events that play a role in tumorigenesis. These activated kinases transmit extracellular signals that ...regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK-ERK-MAPK (RAS-MAPK) pathway has been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. These pathways are considered potential therapeutic targets for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials.
Areas covered:
The biological role of the RAS-MAPK pathway, the consequence of its disregulation and the development of small-molecule inhibitors. The rationale for targeting the RAS-MAPK pathway and the application and the results of various inhibitory molecules as anticancer agents in clinical trials.
Expert opinion:
Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.
The
tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent
alterations are missense mutations that contribute to tumor ...aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream analyses revealed that deletion of mutant
activated the cyclic GMP-AMP Synthase-Stimulator of Interferon Genes pathway but did not cause apoptosis implicating other mechanisms of tumor regression. Furthermore, we determined that only tumors with stable mutant p53 are dependent on mutant p53 for growth.
Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting. Here, we show that, contrary to dogma, MMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior ...clinical response compared to tumors with wild-type p53. Doxorubicin-treated p53 mutant tumors failed to arrest proliferation, leading to abnormal mitoses and cell death, whereas p53 wild-type tumors arrested, avoiding mitotic catastrophe. Senescent tumor cells persisted, secreting senescence-associated cytokines exhibiting autocrine/paracrine activity and mitogenic potential. Wild-type p53 still mediated arrest and inhibited drug response even in the context of heterozygous p53 point mutations or absence of p21. Thus, we show that wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy.
► p53 mutant MMTV-Wnt1 tumors responded to chemotherapy better than p53 wild-type ones ► Wild-type p53 activity induced arrest and senescence, preventing aberrant mitoses ► Treated p53 mutant tumors entered the cell cycle and exhibited aberrant mitosis ► Wild-type p53 mediated arrest and reduced drug response even in the absence of p21
The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location ...may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.
Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to −124 C>T and −146 C>T from the translation start site in the promoter of the telomerase reverse ...transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
...the accessibility of the neck structures to fine needle aspirations and direct or computed tomographic-guided core biopsies allows for effective and initial pathologic assessment diagnostic tools ...11-15. ...the terms ameloblastic carcinoma and odontogenic sarcomas were retained, whereas all other descriptive terms including primary, differentiated, and malignant were omitted. Pathology and genetics of head and neck tumours, 3rd ed., 2005, IARC Press, Lyon 3 S. Fleskens, P. Slootweg, Grading systems in head and neck dysplasias: their prognostic value, weakness and utility, Head Neck Oncol, Vol. 1, 2009, 11 4 N Gale, R. Blagus, S.K. Mofty, Evaluation of new grading system for laryngeal squamous intraepithelial lesions-a proposed useful classification, Histopathology, Vol. 65, 2014, 456-464 5 A.J. Kimple, G.K. Austin, R.N. Shah, Polymorphous low grade adenocarcinoma: a case series and determination of recurrence laryngoscope, Vol. 124, 2014, 2714-2719 6 T.D. Patel, A. Vazquez, E. Marchiano, R.C. Park, S. Barendas, J.A. Eloy, Polymorphous low grade carcinoma of the head and neck: a population-based study of 460 cases, Laryngoscope, Vol. 125, 2016, 1644-1649 7 K.K. Ang, J. Harris, R. Wheeler, Human papillomavirus and survival of patients with oropharyngeal cancer, N Engl J Med, Vol. 363, 2010, 24-35 8 A.K. Chaturvedi, E.A. Engels, R.M. Pfeiffer, Human papillomavirus and rising oropharyngeal cancer incidence in the United States, J Clin Oncol, Vol. 29, 2011, 4294-4301 9 M.L. Gillison, Q. Zhang, R. Jordan, Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer, J Clin Oncol, Vol. 30, 2012, 2102-2111 10 M. Lechner, G.M. Frampton, T. Fenton, Genome Med, Vol. 5, 2013, 49 11 A Ferlito, G Bertino, A Rinaldo, G.M. Mannara, K.O. Deneng, A review of heterotopia and associated salivary glands neoplasms of the head and neck, J Laryngol Otol, Vol. 113, 1999, 299-303 13 J Golledge, H Ellis, The etiology of lateral cervical (branchial) cysts: past and present theories, J Laryngol Otol, Vol. 108, 1994, 653-659 14 J.K. La Plante, N.S. Person, G.L. Hedlund, Radiol Clin N Am, Vol. 53, 2015, 181-196 15 C. Garu, L.V. Johansen, J. Jacobsen, P. Gertsen, E. Andersen, B.B. Jensen, Cervical lymph node metastasis from unknown primary tumors. Suppl. 22, 2014, 6057 18 H. Haack, L.A. Johnson, C.J. Fry, Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody, Am J Surg Pathol, Vol. 33, 2009, 984-991 19 S.C. Huang, B.A. Ghossin, J.A. Bishop, Novel PAX3- NCOA1 fusion in biphenotypic sinonasal sarcoma with focal rhabdomyoblastic differentiation, Am J Surg Pathol, Vol. 40, 2016, 51-59 20 J.T. Lewis, A.M. Oliveria, A.G. Nascimento, Low-grade sino-nasal sarcoma with neural and myogenic features: a clinic-pathologic analysis of 28 cases, Am J Surg Pathol, Vol. 36, 2012, 517-525 21 J.S. Reis-Filho, R. Natrajan, R. Valcheva, Histopathology, Vol. 52, 2008, 840-846 22 A Kalova, T Vancek, R Sima, Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity, Am J Surg Pathol, Vol. 34, 2010, 599-608 23 T. Nagao, T.A. Gaffey, D.W. Vischer, Invasive micropapillary salivary duct carcinoma: a distinct histologic variant with biologic significance, Am J Surg Pathol, Vol. 28, 2004, 319-326 24 D Bell, M.E. Kupferman, M.D. Williams, A Rashid, A.K. El-Naggar, Primary colonic-type adenocarcinoma of the base of tongue: a previously unreported phenotype, Hum Pathol, Vol. 40, 2009, 1798-1802 25 A.M. Gillenwater, H. Fatani, A.K. El-Naggar, Primary intestinal-like adenocarcinoma of major salivary glands: 2 instances of previously undocumented phenotype, Head Neck, Vol. 35, 2013, E234-E236 26 R.H. Spiro, A.G. Huvas, E.W. Strong, Adenocarcinoma of salivary origin.
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