Cabozantinib Overcomes Crizotinib Resistance in ROS1 Fusion–Positive Cancer

Katayama, Ryohei; Kobayashi, Yuka; Friboulet, Luc; Lockerman, Elizabeth L.; Koike, Sumie; Shaw, Alice T.; Engelman, Jeffrey A.; Fujita, Naoya

doi:10.1158/1078-0432.ccr-14-1385

Cited by 183 publications

(157 citation statements)

References 25 publications

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“…This incorrect molecule has been offered by multiple commercial vendors (e.g., Selleck Chemicals; through May, 2016), and several publications cite such vendors as the source of the material used in their study (e.g., see refs. [17][18][19][20].…”

Section: Methodsmentioning

confidence: 99%

The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

Zhang

Anjum

Squillace

et al. 2016

Clinical Cancer Research

283

266

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Purpose: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK þ ) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib. Experimental Design: A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib-ALK co-structure was determined.Results: Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK þ cell lines, brigatinib inhibited native ALK (IC 50 , 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK þ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses. Conclusions: Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK þ , crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials.

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Section: Methodsmentioning

confidence: 99%

The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

Zhang

Anjum

Squillace

et al. 2016

Clinical Cancer Research

283

266

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“…As an inhibitor of MET/RET/VEGFR pathways, cabozantinib revealed activity in alterations resistant to ROS1 inhibitor in a preclinical model. (36,46) …”

Section: Targeting Downstream Effectorsmentioning

confidence: 99%

KRAS and the Reality of Personalized Medicine in Non-Small Cell Lung Cancer

Kılgöz¹,

Bender²,

Scandura³

et al. 2016

Mol Med

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Lung cancer is the leading cause of mortality among all cancer types worldwide. The latest available global statistics of the World Health Organization report 1.59 million casualities in 2012. Worldwide, 1 in 5 cancer deaths are caused by lung cancer. In 2016, in the United States alone, there are an estimated 224,390 new cases of lung cancer, of which 158,080 are expected to result in death, as reported by the National Cancer Institute. Non-small cell lung cancer (NSCLC), a histological subtype, comprises about 85% of all cases, which is nearly 9 out of 10 lung cancer patients. Efforts are under way to develop and improve targeted therapy strategies. Certain mutations are being clinically targeted, such as those in EGFR and ALK genes. However, one of the most frequently mutated genes in NSCLC is the Kirsten rat sarcoma viral oncogene homolog (KRAS), which is currently not targetable. Approximately 25% of all types of NSCLC tumors contain KRAS mutations, which remain as an undruggable challenge. These mutations are indicative of poor prognosis and show negative response to standard chemotherapy. Furthermore, tumors harboring KRAS mutations are unlikely to respond to currently available targeted treatments such as tyrosine kinase inhibitors. Therefore, there is a definitive, urgent need to generate new targeted therapy approaches for KRAS mutations. Current strategies have major limitations and revolve around targeting molecules upstream and downstream of KRAS. Direct targeting is not available in the clinic. Combination therapies using multiple agents are being sought. Concentrated efforts are needed to accelerate basic research and consecutive clinical trials to achieve effective targeting of KRAS. online address: http://www.molmed.org

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“…Cabozantinib is a small molecule inhibitor of tyrosine kinases (Table 1) including MET, VEGF receptors, and AXL [13]. Cabozantinib also inhibits other tyrosine kinases involved in tumor pathology including RET, FLT3, KIT, and ROS1 [13,21]. Similar to other TKIs, cabozantinib is a reversible, ATP-competitive inhibitor.…”

Section: Preclinical Development and Rationalementioning

confidence: 99%