$Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)$

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)

Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The ..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-20-4224

Authors: Jennifer H. Foster, Stephan D. Voss, David C. Hall, Charles G. Minard, Frank M. Balis, Keith Wilner, Stacey L. Berg, Elizabeth Fox, Peter C. Adamson, Susan M. Blaney, Brenda J. Weigel and Yael P. Mossé

Case Study, group4Kirk SmithJuly 1, 2021ALK, neuroblastoma, pediatric, crizotinib

Bonnie Addario shares with the ALK Positive community why we are better together and stronger together; a patient advocate point of view

Bonnie Addario shares with the ALK Positive community why we are better together and stronger together. SEE VIDEO

ALK Positive Inc.

Author: Bonnie Addario

Video, group4Kirk SmithJuly 1, 2021ALKtALK

Actionability of on-target ALK resistance mutations in patients with non-small cell lung cancer: local experience and review of the literature

ALK-fusion-positive NSCLC patients treated with ALK inhibitors frequently develop on-target resistance mutations. We provide clinical evidence for targeting these mutations with currently available inhibitors using a pooled population of 387 patients. The majority achieved clinical benefit, but the likelihood of clinical benefit differed for each mutation-inhibitor combination. Our comprehensive overview can facilitate guidance for treating similar patients in clinical practice. READ ARTICLE

Clinical Lung Cancer DOI: 10.1016/j.cllc.2021.06.011

Authors: Bart Koopman, Harry J.M. Groen, Ed Schuuring, T. Jeroen N. Hiltermann, Wim Timens, Wilfred F.A. den Dunnen, Anke van den Berg, Arja ter Elst, Michel van Kruchten, Joost L. Kluiver, Birgitta I. Hiddinga, Lucie B.M. Hijmering-Kappelle, Matthew R. Groves, Juliana F. Vilacha, Léon C. van Kempen and Anthonie J. van der Wekken

Review Paper, group4Kirk SmithJuly 1, 2021ALK, NSCLC, mutation, resistance, sensitivity

Successful rechallenge of alectinib after remission of severe alectinib-induced interstitial lung disease

Discussion: Given that the ALK inhibitors are the treatment of choice for advanced lung cancer patients with ALK rearrangement. Our report demonstrated the potential feasibility of alectinib re-use in cases of severe druginduced ILD. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220961557

Authors: Huang JR, Chou CW, Chao HS.

group4Kirk SmithJuly 1, 2021

Clinical features and intervention timing in patients with pregnancy-associated non-small-cell lung cancer

Seventy-seven cases were collected including 11 patients from our center. The anaplastic lymphoma kinase (ALK) gene rearrangement and epidermal growth factor receptor (EGFR) mutation rates were 47% and 32%, respectively. The OS of patients treated during pregnancy, after delivery, and those not treated differed significantly [12 months vs. not reached (NR) vs. 1 month; P<0.001]. However, the OS between patients treated during pregnancy and after delivery was similar (P=0.173). Patients with ALK or EGFR exhibited a significantly better OS than those with wild-type [NR vs. 22 months vs. 8 months; P<0.001; hazard ratio (HR) =0.02, 95% confidence interval (CI): 0.00–0.22; HR =0.08, 95% CI: 0.01–0.76]. Fetal complications were observed in babies whose mothers were treated during pregnancy. The pregnancy-associated NSCLC population exhibited a high prevalence of driver genes and a promising effect of targeted therapy. No significant difference in the OS was observed between patients treated..... READ ARTICLE

Journal of Thoracic Disease DOI:10.21037/jtd-21-234

Authors: Lei Yang, Yun-Ting He, Jin Kang, Ming-Ying Zheng, Zhi-Hong Chen, Hong-Hong Yan, Xu-Chao Zhang, Jin-Ji Yang, Yi-Long Wu and Qing Zhou

Exceptional response to the ALK and ROS1 inhibitor lorlatinib and subsequent mechanism of resistance in relapsed ALK F1174L-mutated neuroblastoma

In summary, we describe a patient with relapsed, refractory neuroblastoma harboring the ALK F1174L mutation resistant to the first-generation ALK inhibitor crizotinib combined with chemotherapy in whom lorlatinib induced a durable complete remission of 13 mo. However, as is often the case with targeted therapeutic approaches, resistance, potentially mediated by new genomic alterations including CDK4 and FGFR1 amplification and NRAS mutation, led to disease recurrence. Our case provides an example of clinical benefit made possible by the development of next-generation ALK inhibitors but also highlights the need for increased understanding of mechanisms of acquired resistance. We propose that molecular monitoring during therapy may guide rational combination multidrug approaches to overcome and prevent resistance. READ ARTICLE

Cold Spring Harbor: Molecular Case Studies DOI:10.1101/mcs.a006064

Authors: Tingting Liu, Matthew D., Merguerian, Steven P. Rowe, Christine A. Pratilas, Allen R. Chen and Brian H. Ladle

Case Study, group4Kirk SmithJuly 1, 2021neuroblastoma, pediatric, ALK, lorlatinib, crizotinib combination

E273 Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration Screen reader support enabled.

Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ~10%
of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most
non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage.
Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of b-catenin at EMT gene promoters. We further show that
cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits
cleavage and decreases NB cell migration. Together, our results indicate a pivotal role for WT ALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit. READ ARTICLE

Cell Reports DOI:10.1016/J.CELREP.2021.109363

Authors: Hao Huang, Alexander Gont, Lynn Kee, Ruben Dries, Kathrin Pfeifer, Bandana Sharma, David N. Debruyne, Matthew Harlow, Satyaki Sengupta, Jikui Guan, Caleb M. Yeung, Wenchao Wang, Bengt Hallberg, Ruth H. Palmer, Meredith S. Irwin, Rani E. George

$Case Report: Treatment of Alectinib in NSCLC With Brain Metastasis Patient Refractory to Radiotherapy After Resistance to Crizotinib$

Case Report: Treatment of Alectinib in NSCLC With Brain Metastasis Patient Refractory to Radiotherapy After Resistance to Crizotinib

This case revealed some new insights. First, liquid biopsy is complementary to tissue biopsy in patients with NSCLC, mainly in those with EGFR mutation. However, ALK rearrangement should be assessed using tissue biopsy as much as possible. Second, brain metastasis of NSCLC might respond to second-generation tyrosine kinase inhibitors (TKIs), such as alectinib and ceritinib, after resistance to crizotinib regardless of the presence or absence of ALK rearrangement in liquid biopsy. Finally, combined radiotherapy and TKI therapy appears optimal in patients with brain metastasis of NSCLC after resistance to crizotinib in the absence of a definitive driver gene. READ ARTICLE

Frontiers in Oncology DOI: 10.3389/fonc.2021.709188

Authors: Zhang Chunzhi

Case Study, group4Kirk SmithJune 28, 2021NSCLC, ALK+, radiotherapy

Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)

A series of novel anaplastic lymphoma kinase (ALK) degraders were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking two alectinib analogs (36 and 37) with pomalidomide through linkers of different lengths and types. The most promising degrader 17 possessed a high ALK-binding affinity and potent antiproliferative activity in the ALK-dependent cell lines and did not exhibit obvious cytotoxicity in ALK fusion-negative cells. More importantly, the efficacy of compound 17 in a Karpas 299 xenograft mouse model was further evaluated based on its ALK-sustained degradation ability in vivo. The reduction in tumor weight in the compound 17-treated group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together, our findings suggest that alectinib-based PROTACs associated with the degradation of ALK may have promising beneficial effects for treating ALK-driven malignancies. READ ARTICLE

Journal of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00270

Authors: Shaowen Xie, Yuan Sun, Yulin Liu, Xinnan Li, Xinuo Li, Wenyi Zhong, Feiyan Zhan, Jingjie Zhu, Hong Yao, Dong-Hua Yang, Zhe-Sheng Chen, Jinyi Xu and Shengtao Xu

Pre-Clinical, group4Kirk SmithJune 28, 2021Degradation, Inhibitors, Inhibition, PROTAC, ALK

Response to lorlatinib on a patient with ALK-rearranged non-small cell lung cancer harboring 1151Tins mutation with uterine metastasis

We describe a case of an anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third-generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance. READ ARTICLE

Thoracic Cancer DOI: 10.1111/1759-7714.14056

Authors: Kobayashi T, Kanda S, Fukushima T, Noguchi T, Sekiguchi N and Koizumi T.

Case Study, group4Kirk SmithJune 28, 2021ALK, uterine metastasis, lorlatinib

TGF-β-dependent reprogramming of amino acid metabolism induces epithelial–mesenchymal transition in non-small cell lung cancers

Epithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer. READ ARTICLE

Communications Biology DOI: 10.1038/s42003-021-02323-7

Authors: Fumie Nakasuka, Sho Tabata, Takeharu Sakamoto, Akiyoshi Hirayama, Hiromichi Ebi, Tadaaki Yamada, Ko Umetsu, Maki Ohishi, Ayano Ueno, Hisatsugu Goto, Masahiro Sugimoto, Yasuhiko Nishioka, Yasuhiro Yamada, Masaru Tomita, Atsuo T. Sasaki, Seiji Yano and Tomoyoshi Soga

Pre-Clinical, group4Kirk SmithJune 27, 2021Cancer metabolism, Cancer microenvironment, NSCLC