RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

Niederst, Matthew J.; Sequist, Lecia V.; Poirier, John T.; Mermel, Craig H.; Lockerman, Elizabeth L.; Garcia, Angel R.; Katayama, Ryohei; Costa, Carlotta; Ross, Kenneth N.; Morán, Teresa; Howe, Emily; Fulton, Linnea; Mulvey, Hillary E.; Bernardo, Lindsay A.; Mohamoud, Farhiya; Miyoshi, Norikatsu; VanderLaan, Paul A.; Costa, Daniel B.; Jänne, Pasi A.; Borger, Darrell R.; Ramaswamy, Sridhar; Shioda, Toshi; Iafrate, A. John; Getz, Gad; Rudin, Charles M.; Mino‐Kenudson, Mari; Engelman, Jeffrey A.

doi:10.1038/ncomms7377

Cited by 524 publications

(515 citation statements)

References 38 publications

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“…This phenomenon of transformation has been previously reported in case reports and has been confirmed with repeated biopsies in patient cohorts (59,60,68,69). Clinicians must be aware of this possibility in patients receiving targeted therapies who clinically deteriorate.…”

Section: Mechanisms Of Acquired Resistance To Targeted Cancer Therapiesmentioning

confidence: 63%

“…These biopsies have also been very useful to observe the phenotypic and histological changes of the so-called histological transformation from NSCLC to SCLC (1,3,59) and epithelial-to-mesenchymal transition (EMT) (60). EMT consists of the loss of the epithelial morphology of the neoplastic cells that develop into a form that resembles that of mesenchymal neoplasms.…”

Section: Mechanisms Of Acquired Resistance To Targeted Cancer Therapiesmentioning

confidence: 99%

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Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

Dorantes-Heredia¹,

Ruíz-Morales²,

Cano-García³

2016

Transl. Lung Cancer Res.

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Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3-15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuronspecific enolase.

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Section: Mechanisms Of Acquired Resistance To Targeted Cancer Therapiesmentioning

confidence: 63%

Section: Mechanisms Of Acquired Resistance To Targeted Cancer Therapiesmentioning

confidence: 99%

Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

Dorantes-Heredia¹,

Ruíz-Morales²,

Cano-García³

2016

Transl. Lung Cancer Res.

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“…The RB tumor suppressor is a major negative cell-cycle regulator that is inactivated in approximately 11% of all human cancers, and nearly 100% of SCLC (24,28). Moreover, activated CDK4/6 promotes G 1 -S traversal by phosphorylating and inactivating RB.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression

Bisi

Sorrentino

Roberts

et al. 2016

Molecular Cancer Therapeutics

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Chemotherapy-induced myelosuppression continues to represent the major dose-limiting toxicity of cytotoxic chemotherapy, which can be manifested as neutropenia, lymphopenia, anemia, and thrombocytopenia. As such, myelosuppression is the source of many of the adverse side effects of cancer treatment including infection, sepsis, bleeding, and fatigue, thus resulting in the need for hospitalizations, hematopoietic growth factor support, and transfusions (red blood cells and/or platelets). Moreover, clinical concerns raised by myelosuppression commonly lead to chemotherapy dose reductions, therefore limiting therapeutic dose intensity, and reducing the antitumor effectiveness of the treatment. Currently, the only course of treatment for myelosuppression is growth factor support which is suboptimal. These treatments are lineage specific, do not protect the bone marrow from the chemotherapy-inducing cytotoxic effects, and the safety and toxicity of each agent is extremely specific. Here, we describe the preclinical development of G1T28, a novel potent and selective CDK4/6 inhibitor that transiently and reversibly regulates the proliferation of murine and canine bone marrow hematopoietic stem and progenitor cells and provides multilineage protection from the hematologic toxicity of chemotherapy. Furthermore, G1T28 does not decrease the efficacy of cytotoxic chemotherapy on RB1-deficient tumors. G1T28 is currently in clinical development for the reduction of chemotherapy-induced myelosuppression in first-and second-line treatment of small-cell lung cancer.

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“…Transformation of adenocarcinoma to SCLC in patients with somatic EGFR mutations as the TKI therapy resistance mechanism has previously been reported (15), and the percentage of transformation from adenocarcinoma to SCLC was identified in 14% of cases (7). Analysis of tumor samples and cell lines derived from resistant EGFR mutant patients revealed that RB is lost in 100% of such SCLC transformed cases, but rarely in those that remain NSCLC (16). The gene detection in the present patient following icotinib resistance also revealed RB loss and the appearance of a PIK3CA gene mutation.…”

Section: Discussionmentioning

confidence: 99%

Transformation to small‑cell lung cancer following treatment with icotinib in a patient with lung adenocarcinoma

Chen

Qin

et al. 2018

Oncol Lett

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Abstract. The present study describes the case of a 48-year-old man who was diagnosed with lung adenocarcinoma with an epidermal growth factor receptor (EGFR) 21 L858R mutation. The patient received surgery and adjuvant chemotherapy. When multiple lung metastases appeared, icotinib was administered. Following resistance to icotinib, biopsy by endobroncheal ultrasonography for a right lung hilar lymph node revealed transformation to a neuroendocrine morphology. Neuron-specific enolase (NSE) levels were elevated, accompanied with disease progression following transformation to the neuroendocrine morphology. The post-operative and biopsy specimens were analyzed for 416 genes using next-generation sequencing, and phosphatidylinositol-3-kinase catalytic α mutation and retinoblastoma loss were evident. Five cycles of etoposide combined with cisplatin were administered and a partial response was achieved. The disease progressed again accompanied with an elevated NSE level, and bronchoscopy examination revealed small cell lung cancer (SCLC) after 3 months. The patient received chemotherapy consisting of irinotecan combined with carboplatin for two cycles and achieved stable disease. Overall, a secondary biopsy is important for the evaluation of genetic and histological changes and the selection of an appropriate treatment following tyrosine kinase inhibitor (TKI) resistance, and NSE may be useful for the early detection of SCLC transformation in cases that are resistant to EGFR-TKI therapy. IntroductionLung cancer, including small-cell lung cancer (SCLC) and non-SCLC (NSCLC), which is mainly comprised of adenocarcinoma, squamous cell carcinoma and large cell carcinoma, is the most common type of malignancy and the leading cause of cancer-associated mortality worldwide (1). Adenocarcinoma is the most common type of NSCLC, and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy, including erlotinib, gefitinib or icotinib, is the gold standard of treatment for EGFR-mutant lung adenocarcinoma (2-4). The incidence of EGFR mutation in NSCLC in 2005 was higher in East Asian populations when compared with the incidence in other ethnicities (30 vs. 8%) (5). Patients with lung adenocarcinoma harboring exon 19 deletions achieved longer progression-free survival (PFS) and overall survival time (OS) compared with those with L858R mutations (6). However, patients ultimately develop acquired resistance, and the most recently identified mechanism for this is transformation to SCLC (7). Ahn et al (8) reported six cases of transformation from lung adenocarcinoma to SCLC. Erlotinib, gefitinib, afatinib and icotinib were equally as efficient as each other but exhibited different efficacy-toxicity patterns (4). EGFR-TKI-resistant SCLCs are differentiated early from the lung adenocarcinoma clones that harbor completely inactivated retinoblastoma 1 (RB1) and TP53 (9). Molecular mechanisms involved in the transformation from NSCLC to SCLC include TP53 mutations, RB1 loss, lack of EGFR expression and MYC amplificatio...

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RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

Cited by 524 publications

References 38 publications

Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression

Transformation to small‑cell lung cancer following treatment with icotinib in a patient with lung adenocarcinoma

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