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  • Writer's pictureDr Edin Hamzić

🧬 💊 ROS1 Gene and Tyrosine Kinase Inhibitors: Advancements in Cancer Treatment

Updated: Jan 24

First, let me provide a short outline of the blog post for those interested in a specific section of the blog post so you don’t have to go through the whole post. Also, for those interested in the ROS1 gene, check my blog post about this gene here. Here is the outline of this blog post:

  1. What Are the ROS1 Gene and the ROS1 Receptor Tyrosine Kinase?

  2. The ROS1 Gene and Crizotinib

    1. What Is Crizotinib? What Type of Drug Is Crizotinib? Is Crizotinib Chemotherapy?

    2. What Is the Relation Between Crizotinib and the ROS1 Gene?

    3. How Does Crizotinib Work in the Case of Lung Cancer? How Long Is Crizotinib Effective?

    4. Can Crizotinib Cure Cancer? Is Crizotinib Approved? Is Crizotinib FDA Approved?

    5. What Are the Side Effects of Crizotinib?

  3. The ROS1 Gene and Entrectinib

    1. What Is Entrectinib? What Type of Drug Is Entrectinib?

    2. Who Makes Entrectinib (Rozlytrek)? Who Developed Entrectinib (Rozlytrek)?

    3. What Is the Relation Between Entrectinib and ROS1 Gene?

    4. What Are the Side Effects of Entrectinib?

    5. How Do ROS1 Mutations Affect the Effect of Entrectinib or Vice-Versa?

  4. The ROS1 Gene and Lorlatinib

    1. What Is Lorlatinib? For What Is Lorlatinib Used?

    2. Is Lorlatinib Chemotherapy? Is Lorlatinib FDA Approved? Is Lorlatinib Approved for ROS1?

    3. How Do You Take Lorlatinib?

    4. What Is the Relation Between Lorlatinib and ROS1 Gene?

    5. What Are the Side Effects of Lorlatinib?

How Do ROS1 Mutations Affect the Effect of Lorlatinib or Vice-Versa?



What Are the ROS1 Gene and the ROS1 Receptor Tyrosine Kinase?

  • The ROS proto-oncogene 1, receptor tyrosine kinase, or shortly the ROS1 receptor tyrosine kinase, is a transmembrane receptor protein with unique features involved in processes such as cellular proliferation, differentiation, migration, and cell death [citation].

  • The ROS1 gene encodes the ROS receptor tyrosine kinase, and genetic alterations in the ROS1 gene were associated with different forms of cancer.

  • I published a detailed post about the ROS1 gene, which you can check here, and in this post, I want to present the three tyrosine kinase inhibitors that have been FDA-approved for ROS1-positive tumors and those are:

    • Crizotinib (Xalkori)

    • Entrectinib (Rozlytrek), and

    • Lorlatinib (Lorbrena).

🧬 💊 The ROS1 Gene and Crizotinib

What Is Crizotinib? What Type of Drug Is Crizotinib?

  • Crizotinib is a tyrosine kinase inhibitor (TKI) and an established treatment option for advanced metastatic ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC) [citation].

Is Crizotinib Chemotherapy?

  • No, Cristopinib is a targeted therapy proven to be superior to standard chemotherapy.

What Is the Relationship Between Crizotinib and the ROS1 Gene?

  • Crizotinib (brand name: Xalkori) is effective in non-small cell lung cancer (NSCLC) patients with ROS1 rearrangement. There are benefits to using crizotinib for the treatment of ROS1-positive and Activated anaplastic lymphoma kinase (ALK) positive patients.

  • The ROS1 gene is an oncogene mutated in many solid tumors resulting in the deregulation of a tyrosine kinase–mediated signaling pathway.

  • Interchromosomal and sometimes intrachromosomal rearrangements of the ROS1 gene results in gene fusion of the ROS1 gene with other genes. Gene fusion is, explained in very simple terms, the merging of two genes and the formation of a new hybrid gene from the two previously independent genes.

  • These newly formed hybrid genes can lead to functional changes. In the case of ROS1 gene fusions, it leads to tyrosine kinase activation that further leads to the upregulation of multiple cellular pathways that lead to promoting cell survival and proliferation and eventually onset of cancer.

  • Currently, 26 identified partner genes have been shown to fuse with the ROS1 gene. So, when we say that non-small cell lung cancer (NSCLC) is ROS1 positive, it means that some of these ROS1 genes rearrangements in the form of gene fusions are present, which is the indication for the use of crizotinib for treatment.

  • However, it is essential to note that the emergence of resistance to crizotinib is reported that challenge treatment with crizotinib [citation]. The ROS1 kinase, as well as the ALK kinase, are highly sensitive to selective kinase inhibitors [citation].

How Does Crizotinib Work in the Case of Lung Cancer?

  • As an ATP-competitive small-molecule inhibitor of MET/ALK/ROS1, crizotinib had an impressive objective response rate (ORR) of 72%, median progression-free survival (PFS) of 19.2 months, and overall survival of 51.4 months in patients with advanced metastatic ROS1-rearranged non-small cell lung cancer (NSCLC), and has been clinically proven for the treatment of ROS1-rearranged NSCLC [citation].

  • ROS1 mutation (G2032R) can also emerge in about one-third of patients after crizotinib failure, with another 5% of patients developing another solvent-front substitution, ROS1 D2033N [citation].

Can Crizotinib Cure Cancer?

  • At the beginning of crizotinib treatment, patients benefit. However, the problem arises if the crizotinib resistance mutation occurs [citation].

  • Crizotinib, lorlatinib, and entrectinib are all three FDA-approved drugs. They have significant activity against ROS1-positive non-small cell lung cancer (NSCLC) [citation].


Is Crizotinib FDA Approved?

  • In 2016, the FDA approved crizotinib for ROS1-positive NSCLC patients.

  • Crizotinib is the first tyrosine kinase inhibitor that gained FDA approval to treat advanced ROS1 rearrangement in NSCLC patients [citation].

What Are the Side Effects of Crizotinib?

  • Side effects of crizotinib involve visual impairment, edema, and gastrointestinal toxicities [citation].

How Do ROS1 Mutations Affect the Effect of Crizotinib or Vice-Versa?

  • Acquisition of point mutations in the tyrosine kinase domain of the ROS1 gene can lead to crizotinib resistance.

  • The development of so-called second and third-generation ROS1 inhibitors is forthcoming to solve the problem of resistance [citation].

  • In addition, other active inhibitors are used to treat ROS1-positive and ALK-positive NSCLC patients. These active inhibitors, such as ceritinib, lorlatinib, and entrectinib, are used to overcome the resistance to the first-generation molecule [citation].

  • There are multiple ROS1 mutations conferring resistance to TKIs. The G2032R mutation is the most notable [citation]. Other mutations such as G2032R, G1202R, S1986F, and D2033N are believed to create resistance.

  • The S1986F mutation changes the conformational state of ROS1, which interferes with crizotinib. The D2033N mutation results in a loss of electrostatic potential at the ATP binding site on the receptor inhibiting binding with crizotinib basically disabling contact between ROS1 and crizotinib [citation].

  • Due to the importance of the success of crizotinib therapy, there is a continuous quest for new mutations that potentially interfere with crizotinib.

🧬 💊The ROS1 Gene and Entrectinib

What Is Entrectinib? What Type of Drug Is Entrectinib?

  • Entrectinib (the commercial name is Rozlytrek) is a multikinase inhibitor with potent intracranial activity against ROS1-positive non-small cell lung cancer (NSCLC).

  • Entrectinib gained FDA approval to treat metastatic ROS1-positive non-small cell lung cancer (NSCLC) in August 2019 [citation].

Who Makes Entrectinib (Rozlytrek)? Who Developed Entrectinib (Rozlytrek)?

  • Entrectinib was FDA-approved in August 2019 and it is developed by Chugai Pharmaceutical Co., Ltd (Tokyo, Japan). Manufactured by Genentech USA. Roche is the majority shareholder in Chugai Pharmaceutical, Japan.

What Is the Relation Between Entrectinib and ROS1 Gene?

  • Entrectinib is a ROS1 inhibitor designed to penetrate and remain in the central nervous system. Entrectinib was approved by the US Food and Drug Administration in August 2019 to treat patients with metastatic ROS1 fusion-positive NSCLC [citation].

What Are the Side Effects of Entrectinib?

  • Side effects of entrectinib: dysgeusia, fatigue, constipation, nausea, weight gain, and paresthesia [citation].

How Do ROS1 Mutations Affect the Effect of Entrectinib or Vice-Versa?

  • The drug has shown both systemic and intracranial activity [citation]. Mechanisms of acquired resistance to entrectinib in ROS1-positive non-small cell lung cancer (NSCLC) reportedly include the target kinase domain mutations G2032R, F2004C, and F2004I [citation].

  • As the ROS1-G2032R case was resistant to entrectinib and therefore entrectinib could be effective in patients who have a low risk of ROS1-G2032R development [citation]. Experience with targeted therapy suggests that resistance to entrectinib may potentially limit its effectiveness. The combination of entrectinib and selumetinib may be an effective strategy for treating entrectinib resistance in ROS1-rearranged NSCLC when RAS activation is involved [citation].

🧬 💊The ROS1 Gene and Lorlatinib

What Is Lorlatinib? For What Is Lorlatinib Used?

  • Lorlatinib is a small molecule inhibitor of anaplastic lymphoma kinase (ALK) and the ROS1 kinase developed by Pfizer to treat NSCLC [citation]. Lorlatinib is designed to overcome TKI-resistant ALK mutations and penetrate the blood-brain barrier. However, lorlatinib can also lead to acquired resistance.

Is Lorlatinib Chemotherapy? Is Lorlatinib FDA Approved? Is Lorlatinib Approved for ROS1?

  • Lorlatinib belongs to drugs used in targeted therapy and it is approved for the ROS1-positive cases by FDA in November 2018 [citation].

How Do You Take Lorlatinib?

  • In Japan and the USA, the recommended initial dosage of lorlatinib is 100 mg once daily. The first recommended doses are 75 and 50 mg once daily [citation].

What Is the Relationship Between Lorlatinib and the ROS1 Gene?

  • Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor [citation], selective for ROS1 and ALK with robust penetration into central nervous system.

  • Lorlatinib blocks cancer cell signals to stop the growth of cancer cells.

  • the Lorlatinib is used when chemotherapy is the only alternative treatment [citation].

  • Lorlatinib is approved in the European Union, the US, Canada, and Japan as a monotherapy for treating adult patients with ALK-positive advanced NSCLC [citation].

What Are the Side Effects of Lorlatinib?

  • Some of the most common side effects of lorlatinib are hypercholesterolemia, hypertriglyceridemia, edema, peripheral neuropathy, cognitive effects, weight gain, and dizziness [citation].

How Do ROS1 Mutations Affect the Effect of Lorlatinib or Vice-Versa?

  • Lorlatinib is active for the ROS1-positive population [citation]. According to research, 85.7% percent of the ROS1-positives were considered responders to lorlatinib [citation]. Lorlatinib does not act on the mutation that most commonly causes resistance in the ROS1 gene (G2032R mutation) [citation].



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