Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer

Lovly, Christine M.; McDonald, Nerina T.; Chen, Heidi; Ortiz-Cuarán, Sandra; Heukamp, Lukas C.; Yan, Yingjun; Florin, Alexandra; Ozretić, Luka; Lim, Daryl; Wang, Lu; Zhao, Chen; Chen, Xi; Lu, Pengcheng; Paik, Paul K.; Shen, Ronglai; Jin, Hailing; Buettner, Reinhard; Ansén, Sascha; Perner, Sven; Brockmann, Michael; Bos, Marc; Wolf, Jürgen; Gardizi, Masyar; Wright, Gavin; Solomon, Benjamin; Russell, Prudence A.; Rogers, Toni Maree; Suehara, Yoshiyuki; Red-Brewer, Monica; Tieu, Rudy; Stanchina, Elisa de; Wang, Qingguo; Zhao, Zhongming; Johnson, David H.; Horn, Leora; Wong, Kwok-Kin; Thomas, Roman K.; Ladanyi, Marc; Pao, William

doi:10.1038/nm.3667

Cited by 254 publications

(215 citation statements)

References 32 publications

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“…To determine whether the use of a combination treatment using IGF1R inhibitors and sorafenib is a viable clinical translational strategy to treat HCC, we examined whether ceritinib, an FDA‐approved dual ALK and IGF1R inhibitor for the treatment of non‐small cell lung cancer,17, 18 further sensitizes HCC cells to sorafenib treatment. To do so, we first examined the effect of ceritinib on HCC cell growth, which has not been reported.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Wang

Bank

Malnassy

et al. 2018

Hepatology Communications

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Hepatocellular carcinoma (HCC) is the fifth most common primary cancer and second largest cause of cancer‐related death worldwide. The first‐line oral chemotherapeutic agent sorafenib only increases survival in patients with advanced HCC by less than 3 months. Most patients with advanced HCC have shown limited response rates and survival benefits with sorafenib. Although sorafenib is an inhibitor of multiple kinases, including serine/threonine‐protein kinase c‐Raf, serine/threonine‐protein kinase B‐Raf, vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, and platelet‐derived growth factor receptor β, HCC cells are able to escape from sorafenib treatment using other pathways that the drug insufficiently inhibits. The aim of this study was to identify and target survival and proliferation pathways that enable HCC to escape the antitumor activity of sorafenib. We found that insulin‐like growth factor 1 receptor (IGF1R) remains activated in HCC cells treated with sorafenib. Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B (AKT) activation. Overexpression of constitutively activated AKT reverses the effect of knockdown of IGF1R in sensitizing HCC cells to treatment with sorafenib. Further, we found that ceritinib, a drug approved by the U.S. Food and Drug Administration for treatment of non‐small cell lung cancer, effectively inhibits the IGF1R/AKT pathway and enhances the inhibitory efficacy of sorafenib in human HCC cell growth and survival in vitro, in a xenograft mouse model and in the c‐Met/β‐catenin‐driven HCC mouse model. Conclusion: Our study provides a biochemical basis for evaluation of a new combination treatment that includes IGF1R inhibitors, such as ceritinib and sorafenib, in patients with HCC. (Hepatology Communications 2018;2:732‐746)

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Section: Resultsmentioning

confidence: 99%

“…Although several IGF1R inhibitors have been tested in clinical trials,9, 15, 16 none have been approved by the U.S. Food and Drug Administration (FDA). Intriguingly, ceritinib (Zykadia), a potent anaplastic lymphoma kinase (ALK) inhibitor that is FDA approved for treatment of non‐small cell lung cancer,17 has been reported to effectively inhibit IGF1R 18…”

mentioning

confidence: 99%

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Wang

Bank

Malnassy

et al. 2018

Hepatology Communications

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“…EGFR15 is the most common bypass escape mechanism among these bypass pathways stimulating proliferation independently of ALK, followed by insulin-like growth factor-1 receptor (IGF-1), cKIT, HER2/HER3, and SRC. 3,15,[18][19][20][21] Apart from them, the mTOR activation is also reported to induce resistance crizotinib by increasing autophagia in the ALK receptor ( Figure 1). …”

Section: Bypass Pathwaysmentioning

confidence: 99%

Treatment After Crizotinib Resistance in ALK+ Non-Small-Cell Lung Cancer

Kazaz¹

2017

UHOD

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Systemic chemotherapy, genotype-based targeted therapies and immunotherapy are widely used in the treatment of advanced nonsmall-cell lung cancer (NSCLC). Among the targeted therapies, the agents targeting the epidermal growth factor receptor (EGFR), the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement and C-ros oncogene 1 (ROS-1) have currently become standard treatment for cases presenting such molecular anomalies. Of them, cases with ALKrearrangement displayed dramatic results with a first generation ALK-inhibitor crizotinib; however, most of the patients develop a resistance in a few years. Especially the central nervous system relapses pose the most common clinical problem. Next generation ALK-inhibitors are promising with a high level of effectiveness in this resistance, in which various molecular mechanisms take part. Also, it gains increasing importance to re-perform a biopsy in the progression stage and reveal the mechanisms causing the secondary resistance in those patients. Keywords:Non-small-cell lung cancer, ALK, Crizotinib, Resistance ÖZET ALK-Pozitif Küçük Hücreli Dışı Akciğer Kanserinde Crizotinib Direnci Sonrası Tedaviİleri evre küçük hücreli dışı akciğer kanseri (KHDAK)'nin tedavisinde sistemik kemoterapi, genotipe dayalı hedef tedaviler ve immunoterapi yaygın olarak kullanılmaktadır. Hedef tedaviler arasında epidermal growth factor receptor (EGFR), the echinoderm microtubule-associated protein-like 4 anaplastic lypmhoma kinase (EML4-ALK) rearrangement ve C-ros oncogene 1 (ROS-1)'i hedefleyen ajanlar, bugün için bu moleküler anormalliklere sahip hastalarda standard tedavi haline gelmiştir. Bunlardan ALK-rearrangement'i olan hastalarda birinci jenerasyon ALK-inhibitörü crizotinib ile dramatik sonuçlar elde edilmiş olmakla birlikte hastaların çoğunda birkaç yıl içinde direnç gelişmektedir. Özellikle santral sinir sistemi relapsları en sık karşılaşılan klinik sorun olarak karşımıza çıkmaktadır. Çeşitli moleküler mekanizmaların rol oynadığı bu direnç durumunda yeni jenerasyon ALK-inhibitörleri yüksek etkinlikleri ile ümit vadetmektedir.Ayrıca bu hastalarda progresyon aşamasında tekrar biyopsi yapılması ve sekonder dirence neden olan mekanizmaların ortaya konması giderek önem kazanmaktadır.Anahtar Kelimeler: Küçük hücreli dışı akciğer kanseri, ALK, Crizotinib, Direnç

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“…Amplification of rearranged ALK gene is reported in approximately 15% of crizotinib-refractory patients (14), while activation of EGFR, KRAS, c-KIT or IGF-1R signaling is reported in up to 30% of patients (14,15,69).…”

Section: The Issue Of Acquired Resistance To Crizotinibmentioning

confidence: 99%

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Facchinetti¹,

Tiseo²,

Maïo³

et al. 2016

Transl. Lung Cancer Res.

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Abstract:Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/ RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.

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Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer

Cited by 254 publications

References 32 publications

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Treatment After Crizotinib Resistance in ALK+ Non-Small-Cell Lung Cancer

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

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