Paired genomic analysis of squamous cell carcinoma transformed from EGFR-mutated lung adenocarcinoma

Park, Sehhoon; Shim, Joon Ho; Lee, Boram; Cho, Inju; Park, Woong-Yang; Kim, Youjin; Lee, Se‐Hoon; Choi, Yoon La; Han, Joungho; Ahn, Jin Seok; Ahn, Myung‐Ju; Park, Keunchil; Sun, Jong‐Mu

doi:10.1016/j.lungcan.2019.05.024

Cited by 38 publications

(29 citation statements)

References 34 publications

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“…In a study of surgically resected specimens, PTEN mutations were more often identified in ex‐smokers and in squamous cell carcinomas than in adenocarcinomas . Park et al performed NGS analysis of specimens before and after squamous cell transformation following EGFR‐TKI therapy, and showed genomic alterations in PTEN and PIK3CA in each two of four patients. Another case report by Kuiper et al also showed genomic alteration of PIK3CA in a specimen after squamous cell transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Another case report by Kuiper et al also showed genomic alteration of PIK3CA in a specimen after squamous cell transformation. Park et al hypothesized that the PI3K/AKT/mTOR pathway was activated by EGFR‐TKIs and loss of PTEN , which facilitates cell proliferation and resulted in squamous cell transformation. Interestingly, they found that one of four patients received everolimus (an mTOR (mammalian target of rapamycin) inhibitor) and showed radiological improvement.…”

Section: Discussionmentioning

confidence: 99%

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Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR‐mutated lung adenocarcinoma: a report of two cases

Uruga

Fujii²,

Nakamura

et al. 2020

Respirology Case Reports

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Pathological transformation to squamous cell carcinoma after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment has been reported, but details of the transformation remain unclear. We report two cases with transformation to squamous cell carcinoma. The first case was a 61-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 19 insertion. He experienced squamous cell transformation after 28 months of erlotinib therapy. Next-generation sequencing (NGS) analysis showed EGFR T790M and genomic alterations in PTEN, PDGFR, and HRAS. The second case was a 72-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 21 L858R. He experienced squamous cell transformation after nine months of erlotinib therapy. NGS analysis showed EGFR T790M and genomic alterations in PTEN, SMARCB1, TP53, and KIT. Both patients had PTEN genomic alterations and the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway might play an important role in squamous cell transformation. Case ReportCase 1 A 61-year-old man who was an ex-smoker underwent computed tomography-guided percutaneous lung biopsy. On the basis of the American Joint Committee on Cancer staging

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR‐mutated lung adenocarcinoma: a report of two cases

Uruga

Fujii²,

Nakamura

et al. 2020

Respirology Case Reports

View full text Add to dashboard Cite

show abstract

“…Approximately one percent of EGFR-mutant lung cancer patients develop resistance to EGFR targeting therapeutics that is accompanied by a phenotypic switch from ADC to SCC (Clery et al, 2017;Park et al, 2019). Although SCC is a distinct histological subtype of NSCLC, lung tumors, including those positive for activating mutations in the EGFR gene with mixed adenosquamous histology, are known to occur (Ricciuti et al, 2018).…”

Section: Phenotypic Transformation To Scc As a Mechanism Of Resistancmentioning

confidence: 99%

“…ADC to SCC lineage transformation remains the least common in the setting of acquired resistance to EGFR TKIs, and the exact molecular traits involved in the process are not well-characterized. Available evidence point toward critical involvement of the PI3K/AKT/mTOR signaling axis, where mTOR inhibitors may have an important clinical utility (Park et al, 2019).…”

Section: Phenotypic Transformation To Scc As a Mechanism Of Resistancmentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

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“…A similar situation has been reported in the transformation of ADC to squamous cell carcinoma, and Park et al found that at least one gene mutation involving the PIK3CA pathway was already present before squamous cell carcinoma transformation. 16 It is therefore necessary to be aware of genetic mutations that might predict histological transformation at an early stage, as well as emphasizing the importance of re-biopsy in light of tumor heterogeneity and pathological transformation. Notably, the current patient's circulating tumor DNA revealed three coexisting mutations, T790M, cis-C797S, and EGFR 19 del, as well as inactivation of RB1, at disease progression after the administration of osimertinib.…”

Section: Discussionmentioning

confidence: 99%

Histological transformation of lung adenocarcinoma to small cell lung cancer with mutant C797S conferring acquired resistance to osimertinib

Ren

Cai

et al. 2020

J Int Med Res

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Epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer may initially respond to EGFR tyrosine kinase inhibitors (TKIs), but may subsequently become resistant; however, the resistance mechanisms remain unclear. We report a rare case of acquired resistance to osimertinib associated with transformation to small cell lung cancer (SCLC) with cis-C797S mutation. A man with recurrent lung adenocarcinoma harboring an EGFR exon 19 deletion received erlotinib for 10 months following curative surgery and adjuvant chemotherapy. However, he switched to osimertinib after repeat biopsy showed EGFR exon 19 deletion and T790M mutation leading to erlotinib resistance. His disease progressed after 15 months and repeat biopsy showed SCLC. Next-generation sequencing of peripheral blood detected EGFR exon 19 deletion, T790M mutation, cis-C797S mutation, and RB1 inactivation. The tumor was reduced after four cycles of etoposide and cisplatin and his respiratory symptoms improved. However, computed tomography after six cycles of chemotherapy showed multiple bilateral lung lesions, and single-photon emission computed tomography showed bone metastasis. The patient received paclitaxel plus cisplatin for two cycles with partial response. Because heterogeneous genetic and phenotypic mechanisms of TKI-resistance may occur at different times and locations, histopathological and molecular testing both provide evidence to support appropriate treatment.

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Paired genomic analysis of squamous cell carcinoma transformed from EGFR-mutated lung adenocarcinoma

Cited by 38 publications

References 34 publications

Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR‐mutated lung adenocarcinoma: a report of two cases

Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR‐mutated lung adenocarcinoma: a report of two cases

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Histological transformation of lung adenocarcinoma to small cell lung cancer with mutant C797S conferring acquired resistance to osimertinib

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