Targeted Cancer Treatment (II)

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(2) Brianna Abbott, A New Reality for Terminal Cancer. Patients are living longer; unending treatment casts a shadow. Wall Street Journal, Aug 19, 2025, at page A1.
https://www.msn.com/en-us/health ... rtainty/ar-AA1KHnph

Note:
(a)
(i) Tan AC and Tan DSW, Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations. Journal of Clinical Oncology, 40: 611 (2022; review; authors are based in Singapore)
https://ascopubs.org/doi/10.1200/JCO.21.01626
("Lung cancer has traditionally been classified by histology, with small-cell lung cancer and non–small-cell lung cancer (NSCLC), and NSCLC further consists predominantly of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma. * * * With advances in high-throughput sequencing technologies, particularly next-generation sequencing (NGS), the molecular characterization of NSCLC has revealed a slew of oncogenic alterations (Fig 1), of which several have become targets for drug development.13 This has heralded the era of precision oncology for NSCLC")

(A) Fig 1 caption read in part: "Fig 1. Frequency of targetable oncogenic driver molecular alterations in NSCLC (adenocarcinoma)." Namely, the pie chart excluded small-cell lung cancer and non–small-cell lung cancer (squamous cell carcinoma).

Fig 1A had two concentric circles with outer circle for Asians and inner circle Europeans and North Americans. For lung cancer patients in both populations: "ROS1 Rearrangement (2.6%)."

Nonetheless, you should pencil in rearrangements of NTRK (0.23%), RET (1.7%), ALK (3.8%) -- plus MET exon 14 mutation (3%) and EGFR exon 19 deletion and L858R mutation (46.3% in Asians and 16.3% in Europeans and North Americans). This is because all of these genes (italicized to make them unambiguous) are all RTKs.

L858R is a point mutation at amino acid 858 of the protein where the wild-type L (one-letter symbol for amino acid leucine) is now R (one-letter symbol for amino acid arginine).
(B) Fig 2 showed timeline of drugs available for treatments. Take notice that the same drug may treat several cancers.

Fig 2 caption read in part: "1L, first-line; 2L, second-line." A second-line drug is used after failure of a first-line drug.

"It [entrectinib] is the first FDA-approved treatment designed to target both ROS1 and NTRK that also shows response in cancer that has spread to the brain.[15]"  en.wikipedia.org for entrectinib.
Earlier drug such crizotinib could not penetrate blood-brain barrier (BBB)
(ii) Drilon A et al, Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials, Lancet Oncology, 21: 261 (2020)
https://pubmed.ncbi.nlm.nih.gov/31838015/
(Background: "Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS")
Click the icon on the right margin for the free article.


(b) Before briefing you why first-line drug stopped working for this patient, I will explain how imatinib works in c-abl/ ABL1. At the same time, I also notify you that on Oct 29, 2024, a new class of TKI (tyrosine kinase inhibitor) -- asciminib by Novartis -- was approved by FDA on newly diagnosed or previously treated Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) -- that also concerns c-abl.
(i) Abel A et al, Molecule of the Month: c-Abl Protein Kinase and Imatinib. PDB101, PDB, RCSB, undated ("The article is presented as part of the 2023-2024 PDB-101 health focus on 'Cancer Biology and Therapeutics' ")
https://pdb101.rcsb.org/motm/283
("c-Abl, the target of imatinib, is a [cytoplasmic; ie, it is NOT transmembrane] tyrosine kinase that selectively transfers phosphate groups from ATP to tyrosine. * * * there is a short flexible tail at one [amino or N] end, termed the cap region, that is attached to a myristoyl group. * * * o activate the protein, external cellular signals interact with c-Abl's regulatory domains and release the myristoyl group from the kinase domain, exposing the active site [meaning substrate-binding site, which is distinct from ATP-binding site] and allowing phosphorylation of specific substrates. * * * The 'activation loop' closes over the active site and controls access, and is regulated by a tyrosine that may be phosphorylated. The 'gatekeeper' threonine, the 'DFG Motif,' and several hydrogen bonding amino acids (not shown) are involved in specific interactions with imatinib, helping make the drug more selective. * * * To explore these structures in further detail, click on the JSmol tab [a tab at the top horizontal bar; the resultant new Web page is a still, not a video clip].")
(A) From N- to C-terminus, Abl is composed of cap, SH3 (short for src homology 3 domain), SH2 (short for src homology 2 domain), and kinase domains, followed by the F-actin binding domain (FABD).
(B) For myristoyl, see myristic acid
https://en.wikipedia.org/wiki/Myristic_acid
("The acid is named after the binomial name for nutmeg (Myristica fragrans), from which it was first isolated in 1841 by Lyon Playfair.[12]")
The accent is on the second syllable: ri.
(C) In the middle plate, the cap (covalently attaching a C14 myristoyl group; thecap region is presented as a pink arc) is at 6 o'clock, between c-terminus of kinase domain and the first or N-terminal portion of (brown) "Intrinsically Disordered Region."

Its (middle plate's) caption stated, "ATP is shown in green bound in the active site of the kinase."
(D) You need not learn about gatekeeper threonine or DFG motif.

(ii) Arter C et al (of University of Leeds, England), Structural Features of the Protein Kinase Domain and Targeted Binding by Small-Molecule Inhibitors. Journal of Biological Chemistry, 298: 102247 (2022; review).
https://pubmed.ncbi.nlm.nih.gov/35830914/

Quote:

Abstract: "Most kinase inhibitors are ATP competitive, deriving potency by occupying the deep hydrophobic pocket [ATP-binding site] at the heart of the kinase domain."

Go to Figure 1, whose caption at the last sentence reminded a reader that this figure is Aurora-A, a serine-threonine (protein) kinase -- not c-abl/ ABL1 tyrosine kinase. But these two kinds of kinase are closely related enough to merit discussion together.
Fig 1A has 2 panels, the right panel is obtained by rotating the left panel 90 degrees to the left. Heed the substrating binding site of cucumber shape circumscribed by dots.
Fig 1B is the magnified view of Fig 1A left panel (focusing on the ATP-binding site in the N-lobe of kinase domain), with ATP now presented in BOTH space-filling and stick models, with the three (negatively charged) phosphates of ATP pointing to the right and stabilized by a (positively charged) magnesium ion right below.

Then go straight to Figure 7, whose left panel is ABL1 in complex with both imatinib and "GNF-2 in myristoyl pocket." the paragraph right before this figure stated, "Type IV kinase inhibitors are defined as kinase inhibitors that bind to an allosteric site on the kinase catalytic domain [or substrate-binding site], remote from the ATP site (84). * * * This approach can be exemplified by the development of asciminib (ABL001), the first type IV allosteric inhibitor of BCR-ABL1 to enter clinical trials (85). * * * Asciminib was developed from GNF-2 and GNF-5, the first well-characterized type IV inhibitors of BCR-ABL1, shown to perturb substrate binding through an allosteric mechanism upon compound binding to the C-terminal myristate pocket of ABL1 kinase (Fig. 7) (86)."

(iii) Wu J and Lin Z (both of Chongqing University), Non-Small Cell Lung Cancer Targeted Therapy: Drugs and Mechanisms of Drug Resistance. International Journal of Molecular Sciences, 23: 15056 (2022)
https://pubmed.ncbi.nlm.nih.gov/36499382/
("3.3. Mechanisms of Resistance to ROS1 Inhibitors[:] Point mutations in the ROS1 kinase domain that render ROS1 fusion-positive cancers resistant to ROS1 TKIs [acronym for: tyrosine kinase inhibitors] have been identified * * * Point mutations in the ROS1 kinase domain, such as D2033N, G2032 series, L2026M, L2155S series, and S1986F/Y, can cause acquired resistance to crizotinib [35,124]. * * * Nearly one-third of patients had the most common mutation, ROS1(G2032R). * * * At codon [or amino acid] 2032 in the structural domain of ROS1 kinase, glycine is changed to arginine. This mutation gives resistance to ROS1 kinase inhibition by interfering with drug binding through a spatial site block, while not being present at the gatekeeper residue [129]")

Reference 129 was Awad MM et al. Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1. New England Journal of Medicine, 368: 2395 (2013)
https://www.nejm.org/doi/full/10.1056/NEJMoa1215530
("The glycine at position 2032 is conserved in all human ROS1 paralogs and in several other, more distantly related tyrosine and serine–threonine kinases * * * ROS1 binds crizotinib at the ATP-binding site in the cleft between the N-terminal and C-terminal domains of the kinase.20 * * * An arginine at position 2032 [mutated from wild-type glycine at this position] has been modeled into an empty ROS1 ATP–inhibitor binding site (Figure 3D) and is believed to sterically clash with the piperidine ring of crizotinib while still allowing for ATP binding") (emphasis added)