Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation

Lee, Jake June-Koo; Kim, Tae Min; Koh, Youngil; Lee, Se‐Hoon; Kim, Dong-Wan; Jeon, Yung Jin; Chung, Doo Hyun; Yang, Seung Won; Kim, Young Tae; Kim, Young-Whan; Heo, Dae Seog; Bang, Yung‐Jue

doi:10.1016/j.lungcan.2012.04.012

Cited by 82 publications

(65 citation statements)

References 18 publications

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“…ALK rearrangements and EGFR mutations have largely been reported to be mutually exclusive (3)(4)(5), and as mutual causes of resistance to EGFR tyrosine kinase inhibitors (TKI) or ALK-TKIs (6,7). However, such co-alterations did coexist in some clinical cases (3,8,9). Although the EGFR mutation rate is higher in East Asian patients as compared with Caucasians (10,11), coexistence of ALK rearrangements might be more common in East Asian EGFR mutant patients.…”

Section: Introductionmentioning

confidence: 91%

Lung Cancers with Concomitant EGFR Mutations and ALK Rearrangements: Diverse Responses to EGFR-TKI and Crizotinib in Relation to Diverse Receptors Phosphorylation

Yang

Zhang

et al. 2014

Clinical Cancer Research

145

148

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Purpose: We investigated the incidence of concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements in Chinese patients with non-small cell lung cancer (NSCLC), and assessed responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib in such tumors.Experimental Design: We screened 977 consecutive patients with NSCLC for the presence of concomitant EGFR mutations and ALK rearrangements by rapid amplification of cDNA ends-coupled PCR sequencing and FISH. Immunohistochemistry (IHC) and Western blotting were used to correlate the activation of EGFR, ALK, and downstream proteins with responses to EGFR-TKIs and crizotinib.Results: The overall frequency of concomitant EGFR mutations and ALK rearrangements was 1.3% (13/ 977). EGFR/ALK co-alterations were found in 3.9% (13/336) EGFR-mutant and 18.6% (13/70) ALKrearranged patients. Ten tumors were treated with first-line EGFR-TKIs, with a response rate of 80% (8/10). Two tumors with high phospho-ALK levels and low phospho-EGFR levels achieved stable and progressive disease, respectively. Median progression-free survival was 11.2 months. Coexpression of mutant EGFR and ALK fusion proteins in the same tumor cell populations was detected by IHC. Two cases with high phospho-ALK levels treated with crizotinib achieved partial responses; two cases with low phospho-ALK levels had progressive or stable disease.Conclusion: ALK rearrangements and EGFR mutations could coexist in a small subgroup of NSCLC. Advanced pulmonary adenocarcinomas with such co-alterations could have diverse responses to EGFR-TKIs and crizotinib. Relative phospho-ALK and phospho-EGFR levels could predict the efficacy of EGFR-TKI and crizotinib. Clin Cancer Res; 20(5); 1383-92. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 91%

Lung Cancers with Concomitant EGFR Mutations and ALK Rearrangements: Diverse Responses to EGFR-TKI and Crizotinib in Relation to Diverse Receptors Phosphorylation

Yang

Zhang

et al. 2014

Clinical Cancer Research

145

148

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“…ALK rearrangements and EGFR mutations have been largely reported to be mutually exclusive [1] and as mutual causes of resistance to EGFR tyrosine kinase inhibitors (TKIs) and ALK TKI [4,5]. There is a possibility that similar to the prevalence of EGFR mutations, the coexistence of ALK rearrangement may be higher in East-Asian lung adenocarcinoma patients as compared to the Caucasians [6][7][8]. Recently, rare case reports have emerged noting the coexistence of EGFR mutation in EML4-ALK fusion positive patients [1,[7][8][9][10][11][12].…”

Section: Discussionmentioning

confidence: 99%

“…There is a possibility that similar to the prevalence of EGFR mutations, the coexistence of ALK rearrangement may be higher in East-Asian lung adenocarcinoma patients as compared to the Caucasians [6][7][8]. Recently, rare case reports have emerged noting the coexistence of EGFR mutation in EML4-ALK fusion positive patients [1,[7][8][9][10][11][12]. However, the frequency of such co-alterations is yet to be fully described [9][10][11].…”

Section: Discussionmentioning

confidence: 99%

A Case Report of a Metastatic Adenocarcinoma of Lung with Dual Positivity for EGFR Mutation and ALK Fusion

Kamath¹,

Lokesh²,

K³

2015

J Nucl Med Radiat Ther

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Non-small cell lung cancer ranks among the most lethal cancers worldwide. The rate of epidermal growth factor receptor (EGFR) mutations and echinoderm microtubuleassociated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene fusion is the most common in younger age, non-smoking Asian adenocarcinoma lung cancer patients. EGFR mutations and ALK gene rearrangements are known to be mutually exclusive and as mutual causes of resistance to EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs. However, rarely such co-alterations do co-exist in some clinical cases. Here we report a 62 year old male, heavy smoker with cough, hemoptysis and fatigue. Histopathological examination of bronchoscopic guided biopsy showed adenocarcinoma histology. Staging evaluation, he was found to have stage IV disease on positron emission tomography-computed tomography scan. The biopsy blocks tested positive for both EGFR mutation and ALK fusion. Patient was initiated on tablet Gefitinib 250 mg once daily. To the best of our knowledge, there has been no report of dual EGFR mutation and ALK fusion positivity from India.

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“…20 However, subsequent studies have reported concurrent EGFR mutations and ALK rearrangements in rare NSCLC tumors. 28 In the cohort of 141 NSCLC patients, the percentage of EML4-ALK positivity increased to 33% in patients who were never/light smokers and whose tumors did not contain EGFR mutations. 20 …”

Section: Prevalencementioning

confidence: 96%

Targeted inhibition in tumors with ALK dependency

Kwak¹,

Clark²,

Shaw³

2013

LCTT

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Abstract:The oncogenic function of gene translocations involving the anaplastic lymphoma kinase (ALK) was first reported in rare subtypes of non-Hodgkin's lymphoma almost two decades ago. More recently, aberrant ALK signaling was found to be an oncogenic driver in subsets of non-small cell lung cancer (NSCLC), particularly in patients with little or no tobacco smoking history. The advent of molecularly targeted therapies that inhibit ALK has allowed the pairing of ALK inhibitors such as crizotinib as treatment for ALK-positive NSCLC, yielding dramatic responses and long-term disease control. The clinicopathologic features of ALK-driven NSCLC, the clinical development of ALK inhibitors, and the genetic determinants of acquired resistance to ALK inhibition are among the topics covered in this review.

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Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation

Cited by 82 publications

References 18 publications

Lung Cancers with Concomitant EGFR Mutations and ALK Rearrangements: Diverse Responses to EGFR-TKI and Crizotinib in Relation to Diverse Receptors Phosphorylation

Lung Cancers with Concomitant EGFR Mutations and ALK Rearrangements: Diverse Responses to EGFR-TKI and Crizotinib in Relation to Diverse Receptors Phosphorylation

A Case Report of a Metastatic Adenocarcinoma of Lung with Dual Positivity for EGFR Mutation and ALK Fusion

Targeted inhibition in tumors with ALK dependency

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