Data from Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
Seok-Young KimSang-Min KimSu-Min LimJi Yeon LeeSu-Jin ChoiSan‐Duk YangMi Ran YunChang Gon KimSeo Rin GuChaewon ParkA‐Young ParkSun Min LimSeong Gu HeoHyunki KimByoung Chul Cho
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<div>AbstractPurpose:<p>Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.</p>Experimental Design:<p>Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (<i>n</i> = 12). Organoids were analyzed by whole-exome sequencing (<i>n</i> = 61) and RNA sequencing (<i>n</i> = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.</p>Results:<p>PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non–small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an <i>EGFR</i> exon 19 deletion and a <i>BRAF</i> G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an <i>EGFR</i> L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against <i>ERBB2</i> exon 20 insertions and pralsetinib against <i>RET</i> fusions.</p>Conclusions:<p>We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.</p></div>Keywords:
Afatinib
Trametinib
Targeted Therapy
Dabrafenib
Organoid
T790M
Exome
<div>AbstractPurpose:<p>Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.</p>Experimental Design:<p>Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (<i>n</i> = 12). Organoids were analyzed by whole-exome sequencing (<i>n</i> = 61) and RNA sequencing (<i>n</i> = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.</p>Results:<p>PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non–small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an <i>EGFR</i> exon 19 deletion and a <i>BRAF</i> G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an <i>EGFR</i> L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against <i>ERBB2</i> exon 20 insertions and pralsetinib against <i>RET</i> fusions.</p>Conclusions:<p>We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.</p></div>
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Abstract: EGFR-T790M and BRAFV600E are the common resistance mechanisms to EGFR-tyrosine kinase inhibitors (TKIs). Standard treatment for the triple mutations of EGFR-19del, T790M, and BRAFV600E is still under debate. Herein, we present a case of therapeutic efficacy of osimertinib and dabrafenib plus trametinib on a 63-year-old man with advanced lung adenocarcinoma. This patient reached a remarkable progression-free survival of 9 months without any serious adverse reaction. At the progression of the disease, C797S mutation in cis was detected by liquid biopsy. Subsequently, brigatinib with cetuximab was administered but no curative effect was observed. Then, therapy was changed to apatinib combined with osimertinib. The subsequent CT scan showed that the lesions reached stable disease (SD), and the survival benefit has been evaluated. This case showed that the combination treatment of osimertinib and dabrafenib plus trametinib might be a great treatment option for NSCLC patients with triple mutations ( EGFR-19del/T790M/BRAFV600E ). Keywords: EGFR-19del , T790M , BRAFV600E , EGFR TKI, combination therapy
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<div>AbstractPurpose:<p>Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.</p>Experimental Design:<p>Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (<i>n</i> = 12). Organoids were analyzed by whole-exome sequencing (<i>n</i> = 61) and RNA sequencing (<i>n</i> = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.</p>Results:<p>PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non–small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an <i>EGFR</i> exon 19 deletion and a <i>BRAF</i> G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an <i>EGFR</i> L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against <i>ERBB2</i> exon 20 insertions and pralsetinib against <i>RET</i> fusions.</p>Conclusions:<p>We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.</p></div>
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Targeted Therapy
Dabrafenib
T790M
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Exome
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The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC).In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK).We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790Mtargeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others.Emerging therapies directed against other driver oncogenes in NSCLC including ROS1 , HER2 , and BRAF are covered as well.The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.
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Abstract Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We generated 23 PDCs from 96 malignant effusions of 77 patients with advanced lung adenocarcinoma. Clinical and experimental factors were reviewed to identify determinants for PDC establishment. PDCs were characterized by driver mutations and in vitro sensitivity to targeted therapies. Seven PDCs were analyzed by whole-exome sequencing. PDCs were established at a success rate of 24.0%. Utilizing cytological diagnosis and tumor colony formation can improve the success rate upto 48.8%. In vitro response to a tyrosine kinase inhibitor (TKI) in PDC reflected patient treatment response and contributed to identifying effective therapies. Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.
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Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (n = 12). Organoids were analyzed by whole-exome sequencing (n = 61) and RNA sequencing (n = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non-small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET fusions.We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
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Lorlatinib has been suggested as the therapeutic option for patients with ROS1-rearranged non-small-cell lung cancer (NSCLC) after ROS1 tyrosine kinase inhibitor (TKI) failure. However, the mechanism mediating lorlatinib resistance has not been well elucidated in ROS1-rearranged NSCLC. Post- lorlatinib therapeutic options remain scarce.Herein, we describe a 31-year-old female patient with stage IVB ROS1-rearranged NSCLC. She received 2nd line treatment with crizotinib after chemotherapy failure and achieved a partial response lasting for 15 months. An NF1 p.G127Ter mutation emerged as a potential crizotinib resistance mechanism. She subsequently received lorlatinib treatment and achieved a progression-free survival (PFS) of seven months. Based on the emergence of a resistant BRAF V600E, the patient was switched to a combinatorial targeted therapy with lorlatinib, dabrafenib, and trametinib and attained stable disease. She continued the treatment with a time-to-treatment failure of 5.5 months. The acquisition of NRAS p.Q61R and NTRK amplification may confer resistance to the combinatorial targeted therapy.To the best of our knowledge, we reported the first case demonstrating that BRAF p.V600E can mediate the lorlatinib resistance in ROS1-rearranged NSCLC and the combinational targeted therapy of ROS1 TKI with dabrafenib and trametinib may serve as an efficient therapeutic option for subsequent treatment.
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Lung cancer is a collection of rare diseases, each with its specific genomic abnormalities. Next generation sequencing is a novel diagnostic tool to discover driver mutations. This technology, together with the development of targeted drugs, is rapidly changing our understanding of lung cancer. KRAS gene mutations are the most common mutation in adenocarcinoma of the lung. Patients with ALK rearrangements treated with specific ALK inhibitors such as crizotinib or EGFR-activating mutations treated with gefitinib, erlotinib or afatinib have improved progression-free survival and better quality of life than patients treated with chemotherapy. The latter may subsequently develop tumour resistance, for which novel drugs are rationally designed. In the Netherlands, multidisciplinary tumour boards guide the interpretation of genomic aberrations and the use of registered and off-label targeted drugs.
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