MET-Targeting Anticancer Drugs—De Novo Design and Identification by Drug Repurposing

Round 1

Reviewer 1 Report

This is an extremely well written and comprehensive review which was a pleasure to read. I do have a number of minor siuggestions that might help improve the manuscript

 

 1.    Line 25 The part on drug repurposing doesn’t really flow well from the previous section of the abstract which is focused on Met. Related to this, lines 73-76 seem to be identical to this part of the introduction. It would be better to reword one these.

 

2.    Line 60 It would be helpful to know what the exon-skipping does to Met activity/regulation. It would help the reader understand the significance of the mutations.

3.    Line 106 There is an extra full stop at the start of the title. Same on line 340, 360,676 600…at this point I have stopped noting these. Please check the rest of the manuscript

4.    Line 148. The explanation of veri-stat is unclear. What proteomic signature?

5.    Line 156 delete “indeed”

6.    Line 160 What is the relevance of the anti HS domain?

7.    Line 185 What does “Met>60% expression” mean?

8.    Line 187 Do you mean defucosylated?

9.    Lone 196 stable disease in how many patients?

10.  Line 233 The section on MvDN30) is a little confusing, I don’t really understand why one domain removes HGF from the cell surface and the other sequesters Met. Surely both will carry out both functions? Would a diagram be helpful?

11.  Table1 Many of the TKIs are multi-targetted. It would be helpful to have an indication of their rank order of potency at different kinases. Eg how does the affinity of crizotinib compare for Met, Ron and Alk.

12.  The different types of TKI are described on lines 367-380, but then this is repeated when each of the examples of  types I II, III TKI are discussed. There is no need to say the same thing twice. I would suggest integrating the material in 367-380 into the later paragraphs.

13.  Line 510 by kinase binding site, do they mean the ATP binding site?

14.  Loine 560 what does D1228X or Y1230X mean – that the residue can change to any amino acid? (What does the X signify?)

15.  Line 579 Do you mean nanomolar?

16.          The symbol “alpha” seems to have been altered in several places throughout the manuscript (egthe section on alpha C helix, also line808,811 848) I suggest checking the entire manuscript for this.

Author Response

Reviewer 1 Comments:

This is an extremely well written and comprehensive review which was a pleasure to read. I do have a number of minor suggestions that might help improve the manuscript

 

1. Line 25 The part on drug repurposing doesn’t really flow well from the previous section of the abstract which is focused on Met. Related to this, lines 73-76 seem to be identical to this part of the introduction. It would be better to reword one these.

Response:

Thank you so much for the positive comment and valuable suggestions from the reviewer. To avoid duplication, the few sentences from line 25-26 were deleted. Lines 81-83 (i.e., lines 73-76 in original submission) remain unchanged.

 

2. Line 60 It would be helpful to know what the exon-skipping does to Met activity/regulation. It would help the reader understand the significance of the mutations.

Response:

The effect of exon skipping on Met regulation is described briefly on lines 67-70.

 

3. Line 106 There is an extra full stop at the start of the title. Same on line 340, 360,676 600…at this point I have stopped noting these. Please check the rest of the manuscript

Response:

Thank you for picking up the mistakes. The extra full stop in various places is now removed.

 

4. Line 148. The explanation of veri-stat is unclear. What proteomic signature?

Response:

The information about veri-stat is elaborated (lines 161-165).

 

5. Line 156 delete “indeed”

Response:

The word “indeed” is deleted (line 170).

 

6. Line 160 What is the relevance of the anti HS domain?

Response:

The HSA binding domain serves as a carrier to extent the half-life and leads to a more favorable pharmacokinetic profile (lines 174-176).

 

7. Line 185 What does “Met>60% expression” mean?

Response:

“Met>60% expression” refers to high tumor Met protein expression (i.e., >60% of cells expressing Met at >2+ IHC staining intensity) (lines 201-202).

 

8. Line 187 Do you mean defucosylated?

Response:

The word is corrected as “afucosylated” (line 204).

 

9. Lone 196 stable disease in how many patients?

Response:

In the phase 1 clinical trial, one patient (1 out of 16) with metastatic, MET-amplified gastric cancer refractory to platinum and taxane-based chemotherapy maintained stable disease for 6 months following treatment with ARGX-111 (lines 213-215).

 

10. Line 233 The section on MvDN30) is a little confusing, I don’t really understand why one domain removes HGF from the cell surface and the other sequesters Met. Surely both will carry out both functions? Would a diagram be helpful?

Response:

An additional figure (Figure 2) is included to illustrate the effect of the MvDN30-decoyMET hybrid molecule. As this new figure is added, the original Fig 2 & 3 are renamed as Fig 3 & 4.

 

11. Table1 Many of the TKIs are multi-targetted. It would be helpful to have an indication of their rank order of potency at different kinases. Eg how does the affinity of crizotinib compare for Met, Ron and Alk.

Response:

The relative rank of target inhibition is shown according to Ki value in Table 1.

 

12. The different types of TKI are described on lines 367-380, but then this is repeated when each of the examples of types I II, III TKI are discussed. There is no need to say the same thing twice. I would suggest integrating the material in 367-380 into the later paragraphs.

Response:

The suggestion from the reviewer is well taken. The description about the different types of TKI is now removed from section 2.3.1-2.3.4 to avoid duplication.

 

13. Line 510 by kinase binding site, do they mean the ATP binding site?

Response:

“ATP binding site” is included in the sentence (line 568).

 

14. Loine 560 what does D1228X or Y1230X mean – that the residue can change to any amino acid? (What does the X signify?)

Response:

The various mutated amino acids are now specified as “D1228X(N/H/Y/E)” and “Y1230X(C/H/N/S)” (line 620).

 

15. Line 579 Do you mean nanomolar?

Response:

The unit is corrected as “nM” (line 639).

 

16. The symbol “alpha” seems to have been altered in several places throughout the manuscript (egthe section on alpha C helix, also line808,811 848) I suggest checking the entire manuscript for this.

Response:

The missing special symbol for “alpha” or “beta” is included back in appropriate places (lines 667, 671, 879, 882, 920).

 

Reviewer 2 Report

Dear authors,

the review in object represents the state of the art of MET tirosin-kinase inhibitors used to treat cancers in preclinical and clinical trials. In my opinion, this paper allows the reader to clearly understand the mechanisms underlying MET dysregulation in tumor cells, the potential biological targets and therapeutic approaches.

 

 

 

Author Response

Reviewer 2 Comments:

Dear authors,

the review in object represents the state of the art of MET tirosin-kinase inhibitors used to treat cancers in preclinical and clinical trials. In my opinion, this paper allows the reader to clearly understand the mechanisms underlying MET dysregulation in tumor cells, the potential biological targets and therapeutic approaches.

 

Response:

Thank you so much for the positive comment from the reviewer. No specific revision is requested by this reviewer.