PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

Zou, Helen Y.; Friboulet, Luc; Kodack, David P.; Engstrom, Lars D.; Li, Qiuhua; West, Melissa; Tang, Ruth W.; Wang, Hui; Tsaparikos, Konstantinos; Wang, Jinwei; Timofeevski, Sergei; Katayama, Ryohei; Dinh, Dac M.; Lam, Hieu; Lam, Justine L.; Yamazaki, Shinji; Hu, Wenyue; Patel, Bijal; Bezwada, Divya; Frias, Rosa L.; Lifshits, Eugene; Mahmood, Sajid; Gainor, Justin F.; Affolter, Timothy; Lappin, Patrick B.; Gukasyan, Hovhannes J.; Lee, Nathan; Deng, Shibing; Jain, Rakesh K.; Johnson, Ted W.; Shaw, Alice T.; Fantin, Valeria R.; Smeal, Tod

doi:10.1016/j.ccell.2015.05.010

Cited by 392 publications

(355 citation statements)

References 46 publications

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“…In line with this, homology alignment showed that TRKA p.G595R is analogous to ALK p.G1202R, whereas TRKA p.G667C is analogous to ALK p.G1269A. Accordingly, ALK p.G1269A, which mediates resistance to crizotinib, can be overcome with second-generation ALK inhibitors, such as ceritinib and alectinib, whereas both are ineffective on ALK p.G1202R (17)(18)(19). Analogously, at clinically achievable doses, entrectinib still retains a partial effect on p.G667C but not on p.G595R TRKA.…”

Section: Research Briefmentioning

confidence: 63%

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Russo

Misale

Ge³

et al. 2016

Cancer Discovery

261

265

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Entrectinib is a fi rst-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA-NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profi ling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1 , p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confi rmed that either mutation renders the TRKA kinase insensitive to entrectinib. These fi ndings can be immediately exploited to design next-generation TRKA inhibitors. SIGNIFICANCE:We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identifi cation of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the fi rst time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements. Cancer Discov; 6(1);[36][37][38][39][40][41][42][43][44]

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Section: Research Briefmentioning

confidence: 63%

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Russo

Misale

Ge³

et al. 2016

Cancer Discovery

261

265

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“…Of course, other ALK‐targeting drugs are in various stages of development like AP26113 and PF‐06463922. They have been specifically designed to have outstanding CNS penetration, and are anticipated to be applied in future 86, 87. Figure 2 provides ALK and brain metastasis, including occurrence, development, and some representative drugs.…”

Section: The Mechanism Of Brain Metastasismentioning

confidence: 99%

Emerging findings into molecular mechanism of brain metastasis

Chen

2018

Cancer Medicine

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Brain metastasis is an important cause of morbidity and mortality in cancer patients. Hence, the need to develop improved therapies to prevent and treat metastasis to the brain is becoming urgent. Recent studies in this area are bringing about some advanced progress on brain metastasis. It was concluded that the occurrence and poor prognosis of brain metastasis have been mostly attributed to the exclusion of anticancer drugs from the brain by the blood‐brain barrier. And several highly potent new generation targeted drugs with enhanced CNS distribution have been developed constantly. However, the noted “seed and soil” hypothesis also suggests that the outcome of metastasis depends on the relationship between unique tumor cells and the specific organ microenvironment. Moreover, increasing studies in multiple tumor types demonstrated that brain metastasis has great molecular differences between primary tumors and extracranial metastasis to a large extent. Here, the authors summarized the most common malignancies that could lead to brain metastasis—lung cancer, breast cancer and melanoma and their related mutated factors. Only by comprehending a deeper understanding of the molecular mechanisms, more effective brain‐specific therapies will be developed for brain metastasis.

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“…Preclinical data shows that it is more potent than crizotinib, ceritinib, and alectinib with in vivo activity against the highly resistant G1202R mutation, which is resistant to the other TKIs, including brigatinib [36]. At the 2017 American Society for Clinical Oncology (ASCO) meeting, Shaw et al presented the preliminary data for the phase I/II trial of lorlatinib in ALK -positive patients who had received one or more prior ALK TKI.…”

Section: Therapeutic Optionsmentioning

confidence: 99%

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Qin

Gadgeel

2017

Targ Oncol

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Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

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PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

Cited by 392 publications

References 46 publications

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Emerging findings into molecular mechanism of brain metastasis

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

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