Investigate Bortezomib signature in the context of other proteasomal inhibitors

[shntnu]

We've received some insightful feedback from reviewers on our paper. Here, we will address two major comments:

Reviewer 2 - Major Comment 6.
Interestingly, the Bortezomib signature is specific to the drug and not a broad range of proteasomal inhibitors. However, seeing the common features between all the proteasomal inhibitors would be interesting.

Reviewer 3 - Major Comment 4
There was some predictive ability of the Bortezomib Signature for ixazomib resistance. Were there some features that were correlated with IX-resistance, i.e. UPS pathway, versus specific to bortezomib? Do the features suggest anything about resistance mechanisms or is the feature set too abstruse to interpret?

Next steps: @yhan8 will outline the analysis that's needed, seeking inputs from @gwaybio and @shntnu as needed, and then perform the analysis.

[gwaybio]

Sounds good @shntnu and @yhan8 !

Would you be able to complete this analysis by July 17th? If not, then all we need is an outline of the planned analyses and a commitment that you will perform this analysis after editorial review of our review plan. Thanks!

[yhan8]

Sounds good @shntnu and @yhan8 !

Would you be able to complete this analysis by July 17th? If not, then all we need is an outline of the planned analyses and a commitment that you will perform this analysis after editorial review of our review plan. Thanks!

@shntnu and I will meet next week to determine the nature of the analyses (e.g., time commitment, and whether it is straightforward for me to run some of your scripts etc), we will update you. @gwaybio

[shntnu]

Interestingly, the Bortezomib signature is specific to the drug and not a broad range of proteasomal inhibitors. However, seeing the common features between all the proteasomal inhibitors would be interesting.

@gwaybio – @yhan8 and I are discussing this right now. For both analyses in this issue, we need the Bortezomib and Ixazomib signatures. The Bortezomib signature is calculated here. But it doesn't appear that we create an Ixazomib signature. Can you confirm this? I haven't looked carefully; Yu is reasonably confident that we had it only for Bortezomib but we wanted to double check with you.

[gwaybio]

I looked when I put together the Review Plan, and I also couldn't find this. I could have sworn that I had already done this, but I must be hallucinating.

[shntnu]

Here are the IX-related profiles in case we want to do anything further here (more in the Review plan)

df <- list.files("~/Downloads/profiling-resistance-mechanisms-master/0.generate-profiles/metadata", full.names = T, recursive = T, pattern ="*.txt") %>% map(function(f) read_tsv(f, show_col_types = FALSE, col_types = cols(.default = "c")))|> list_rbind()

df %>% count(clone_number, treatment) %>% filter(str_detect(clone_number, "Ixa") | str_detect(treatment, "Ixa")) %>% knitr::kable()

clone_number	treatment	n
Ixazomib clone 01	0.1% DMSO	18
Ixazomib clone 01	50 nM Ixazomib	18
Ixazomib clone 02	0.1% DMSO	18
Ixazomib clone 02	50 nM Ixazomib	18
Ixazomib clone 03	0.1% DMSO	18
Ixazomib clone 03	50 nM Ixazomib	18
Ixazomib clone 04	0.1% DMSO	18
Ixazomib clone 04	50 nM Ixazomib	18
Ixazomib clone 05	0.1% DMSO	18
Ixazomib clone 05	50 nM Ixazomib	18
WT clone 04	50 nM Ixazomib	18
WT clone 05	50 nM Ixazomib	18
WT clone 06	50 nM Ixazomib	18
WT clone 07	50 nM Ixazomib	18
WT parental	50 nM Ixazomib	18

 df %>% count(plate_map_name, clone_number, treatment) %>% filter(str_detect(clone_number, "Ixa") | str_detect(treatment, "Ixa")) %>% knitr::kable()

plate_map_name	clone_number	treatment	n
218698	Ixazomib clone 01	0.1% DMSO	6
218698	Ixazomib clone 02	0.1% DMSO	6
218698	Ixazomib clone 03	0.1% DMSO	6
218698	Ixazomib clone 04	0.1% DMSO	6
218698	Ixazomib clone 05	0.1% DMSO	6
218699	Ixazomib clone 01	50 nM Ixazomib	6
218699	Ixazomib clone 02	50 nM Ixazomib	6
218699	Ixazomib clone 03	50 nM Ixazomib	6
218699	Ixazomib clone 04	50 nM Ixazomib	6
218699	Ixazomib clone 05	50 nM Ixazomib	6
218699	WT clone 04	50 nM Ixazomib	6
218699	WT clone 05	50 nM Ixazomib	6
218699	WT clone 06	50 nM Ixazomib	6
218699	WT clone 07	50 nM Ixazomib	6
218699	WT parental	50 nM Ixazomib	6
218854	Ixazomib clone 01	0.1% DMSO	6
218854	Ixazomib clone 02	0.1% DMSO	6
218854	Ixazomib clone 03	0.1% DMSO	6
218854	Ixazomib clone 04	0.1% DMSO	6
218854	Ixazomib clone 05	0.1% DMSO	6
218855	Ixazomib clone 01	50 nM Ixazomib	6
218855	Ixazomib clone 02	50 nM Ixazomib	6
218855	Ixazomib clone 03	50 nM Ixazomib	6
218855	Ixazomib clone 04	50 nM Ixazomib	6
218855	Ixazomib clone 05	50 nM Ixazomib	6
218855	WT clone 04	50 nM Ixazomib	6
218855	WT clone 05	50 nM Ixazomib	6
218855	WT clone 06	50 nM Ixazomib	6
218855	WT clone 07	50 nM Ixazomib	6
218855	WT parental	50 nM Ixazomib	6
218858	Ixazomib clone 01	0.1% DMSO	6
218858	Ixazomib clone 02	0.1% DMSO	6
218858	Ixazomib clone 03	0.1% DMSO	6
218858	Ixazomib clone 04	0.1% DMSO	6
218858	Ixazomib clone 05	0.1% DMSO	6
218859	Ixazomib clone 01	50 nM Ixazomib	6
218859	Ixazomib clone 02	50 nM Ixazomib	6
218859	Ixazomib clone 03	50 nM Ixazomib	6
218859	Ixazomib clone 04	50 nM Ixazomib	6
218859	Ixazomib clone 05	50 nM Ixazomib	6
218859	WT clone 04	50 nM Ixazomib	6
218859	WT clone 05	50 nM Ixazomib	6
218859	WT clone 06	50 nM Ixazomib	6
218859	WT clone 07	50 nM Ixazomib	6
218859	WT parental	50 nM Ixazomib	6