Heterogeneous responses and resistant mechanisms to crizotinib in <i>ALK</i>‐positive advanced non‐small cell lung cancer

Kang, Jin Hyung; Chen, Hua-Jun; Zhang, Xuchao; Su, Jian; Zhou, Qing; Tu, Hai‐Yan; Wang, Zhen; Wang, Bin-Chao; Zhong, Wen‐Zhao; Yang, Xue‐Ning; Chen, Zhihong; Ding, Yan; Wu, Xue; Wang, Mei; Fu, Jiangang; Yang, Zhenfan; Zhang, Xian; Shao, Yang; Wu, Yi‐Long; Yang, Jing

doi:10.1111/1759-7714.12791

Cited by 16 publications

(18 citation statements)

References 25 publications

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“…Intrinsic and acquired resistance mechanisms are highly heterogeneous. In the case of crizotinib, several studies reported mechanisms of acquired resistance mainly involving mutations in the ALK gene (26). In this study, we were able to obtain only one postbiopsy from a patient with acquired resistance and an ALK-G1220R mutation was detected which is known to induce crizotinib resistance.…”

Section: Discussionmentioning

confidence: 93%

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Tertre

Marques

Tremblay

et al. 2019

Molecular Cancer Therapeutics

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Rearrangements in the anaplastic lymphoma kinase (ALK) gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC). Here, we present a comprehensive genomic landscape of 11 patients with ALKþ NSCLC and investigate its relationship with response to crizotinib. Using wholeexome sequencing and RNAseq data, we identified four rare ALK fusion partners (HIP1, GCC2, ERC1, and SLC16A7) and one novel partner (CEP55). At the mutation level, TP53 was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of ALK or gain in EGFR was associated with shorter PFS. This study is the first to report a comprehensive view of the ALKþ NSCLC copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of TP53 mutation as a strong prognostic indication of poor clinical response in ALKþ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALKþ NSCLC.

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Section: Discussionmentioning

confidence: 93%

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Tertre

Marques

Tremblay

et al. 2019

Molecular Cancer Therapeutics

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“…The most frequently disrupted gene was TP53, even though, due to the low amount of pre-therapy samples to be matched, it is not clear if these mutations may pre-exist the development of resistance. Among other genes, rare private alterations at low frequency were identified in BRAF, FGFR2, MET, NRAS and PIK3CA genes (8,34). Among the others, mutations of POLE gene that encodes the catalytic subunit of DNA polymerase epsilon, permissive of the accumulation of a high number of somatic mutations, have been detected in post-crizotinib specimens (34).…”

Section: Co-occurring Mutationsmentioning

confidence: 99%

“…Among other genes, rare private alterations at low frequency were identified in BRAF, FGFR2, MET, NRAS and PIK3CA genes (8,34). Among the others, mutations of POLE gene that encodes the catalytic subunit of DNA polymerase epsilon, permissive of the accumulation of a high number of somatic mutations, have been detected in post-crizotinib specimens (34). In a post-ceritinib patient-derived cell line a MAP2K1-K57N mutation was identified and it conferred sensitivity to the dual blockade of ALKi plus selumetinib (MEKi) (35).…”

Section: Co-occurring Mutationsmentioning

confidence: 99%

Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won

Tabbò¹,

Reale²,

Bironzo³

et al. 2020

Transl Lung Cancer Res

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Anaplastic lymphoma kinase (ALK) translocations are responsible of neoplastic transformation in a limited subset of non-small cell lung cancer (NSCLC) patients. In recent years outcomes of these patients improved due to the development and clinical availability of specific and extremely active targeted therapies [i.e., next-generation Tyrosine Kinase Inhibitors (TKI)]: ALK+ patients are now reaching impressive results when treated with more potent inhibitors upfront with an average median progression-free survival (mPFS) around 35 months. However, under drug pressure, cancer cells develop resistance and patients eventually progress. Multiple mechanisms of intrinsic or acquired resistance have been extensively characterized. Less potent ALK inhibitors (ALKi)-like crizotinib-usually tend to induce a large spectrum of secondary intrakinase mutations; however, these alterations may be observed also after sequential administration of multiple ALKi. Noteworthy, neoplastic cells may evade ALK targeting through a myriad of different mechanisms involving cell-stroma interaction, activation of parallel signaling pathways, intracellular downstream adaptation and histological reshaping, as relevant molecular events. Often these phenomena are restricted to a limited number of cases or even can be patient-specific, thus hindering the development of therapeutic strategies largely applicable. Consequently, the recognition of specific resistance mechanisms seldom translates in clinical opportunities. Management of ALK+ patients is drastically changed and deciphering the molecular biology underlying this disease during treatment is of paramount relevance. The bedrock of resistance to TKI is that, after the diagnosis, we face with a different disease that needs to be re-characterized through tissue or/and liquid biopsies. Understanding molecular pathways driving the resistant phenotype will give us the chance to know what we are dealing with and, rather than choose an empirical approach, will help us to properly define the best targeted treatment for these patients.

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“…33 ALK alterations were detected by Thoracic Cancer 11 (2020) 346-352 fluorescence in situ hybridization with ALK break apart probes and/or immunohistochemistry (IHC) staining with Ventana anti-ALK antibody as previously described. 34…”

Section: Genetic Analysismentioning

confidence: 99%

Low frequency of mutation of epidermal growth factor receptor (EGFR) and arrangement of anaplastic lymphoma kinase (ALK) in primary pulmonary lymphoepithelioma‐like carcinoma

Yin

Feng

et al. 2019

Thoracic Cancer

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Background: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and unique subtype of lung cancer. However, the prevalence of driver alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, and the response of tyrosine kinase inhibitor (TKIs) in PLELC has not been thoroughly investigated. Method: We retrospectively reviewed the genetic profiles and treatment course of 330 PLELC patients at the Guangdong Lung Cancer Institute (GLCI) from based on their mention of "driver mutations" and "the response of TKIs to mutant PLELC". Results: Genetic alterations of EGFR/ALK were tested in 203 patients (203/330, 61.5%). Five patients (5/175, 2.9%) had EGFR mutation and three patients (3/140, 2.1%) had ALK alteration. From the total of 15 articles identified from electronic searches, 1071 PLELC cases mentioned the driver mutations. EGFR mutation and ALK rearrangement were detected in 15 patients and one patient, respectively. In total, there were four EGFR/ALK mutant PLELC patients who received targeted therapy as palliative treatment at the GLCI and in the literature. However, there was disease progression in all cases one month after use of TKIs. Conclusion: The mutation rates of EGFR and ALK were low in PLELC. EGFR and ALK TKIs showed limited response in EGFR/ALK mutant PLELC. Further studies are needed to explore other molecular targets to optimize the therapeutic strategy for PLELC. Key points• The mutation rates of EGFR and ALK in PLELC were lower than other common types of non-small cell lung cancer. • EGFR/ALK TKIs showed a limited response in EGFR/ALK mutant PLELC.• This large cohort study demonstrates the prevalence of EGFR mutation and ALK alteration, and summarizes the response of targeted therapy in mutant PLELC patients.

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Heterogeneous responses and resistant mechanisms to crizotinib in ALK‐positive advanced non‐small cell lung cancer

Cited by 16 publications

References 25 publications

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won

Low frequency of mutation of epidermal growth factor receptor (EGFR) and arrangement of anaplastic lymphoma kinase (ALK) in primary pulmonary lymphoepithelioma‐like carcinoma

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