HRAS Q61L Mutation as a Possible Target for Non-Small Cell Lung Cancer: Case Series and Review of Literature
, Guillaume Herbreteau 2, Siméon Robin 3, Charlotte Fenat 3, Jaafar Bennouna 4, Christophe Blanquart 5, Marc Denis 2 and Elvire Pons-Tostivint 1,5,*,†Round 1
Reviewer 1 Report
This is a well written case report dealing with potentially treating lung cancers with Ha Ras mutations with the farnesyltransferase inhibitor Tipifarnatib. Mutations in Ha Ras are quite rare in NSCLC (<1%) in contrast with the fact that they are much more commonly mutated in bladder, head and neck and thyroid cancer.
There are a number of somewhat specific questions which the authors might address in any revised manuscript:
- Tipifarnatib Effects The Prenylation and Membrane Processing of HaRas In Contrast To EGFR Inhibitors Or THe Ki Ras Inhibitors Which Target The Direct Function Of The Target Enzymes. Although this difference may be somewhat specific most investigators, reading this article , might be more knowledgeable about these more direct inhibitors. However both the preclinical data (e.g. Gilardi et al Mol. Cancer Therapeu 1784-96 (2020) ) and the promising clinical data in Head and neck and bladder (which the authors reference) show that you can target cells with Ha Ras mutations even though one has not directly targeted the enzyme. The other interesting aspect of these observations is that whereas toxicities with the direct enzyme inhibitors e.g. EGFR inhibitors is due to inhibition of the target enzumes in non targeted cells with Tipifarnatib it is probably due to inhibition of various other farnesylated proteins in addition to Ha Ras.
- In Head and Neck , Thyroid and Bladder Cancers Ha Ras Mutations Are Relatively Common and are likely to be Driving Mutations. In the four cases of Lung cancers in Table 3 two have mutations in Ki Ras which we might expect to be the driving mutations. hus, it becomes the interesting question whether despite the fact that the tumors had Ha Ras mutations the question remains would they strongly respond to Tipifarnatib. It's worth a few lines of discussion but can only be determined climially.
- Because of the Rarity of HaRas Mutations in NSCLC Approaches Examining Cell lines or PDX samples are probably not applicable. Worth a two line comment perhaps. .
- Are Ha Ras Mutations in NSCLC More Common In Squmous Cell vs Adenocarcinomas. The data of the authors are consistent with most or all samples being Adenocarcinomas. Whereas some of the literature (albeit rare) were associated with Squamous cell cancer as was a specific trial being performed in SCC of the lung with Ha Ras mutations.
Author Response
Please see the attachment.
Author Response File: 
Author Response.docx
Reviewer 2 Report
In this paper authors focused on the potential role of HRAS Q61L mutation in Non-Small Cell Lung Cancer.
The topic is interesting but several aspects have to be better investigated and discussed.
-First, the title is misleading, authors do not specifically discuss the predictive role of HRAS Q61L mutation, they only describe clinical pathological features of four patients harbouring this mutation alone or in combination with other alterations and treated in different ways.
-Authors should integrate and complete this study with data about HRAS mutations in NSCLC from The Cancer Genome Atlas.
-What about NGS test? Could authors report more details (NGS panel and platform, type of samples, etc…)?
- Supp Table 1 is missing.
- Authors should report the variant allele frequency of identified alterations.
-HRAS Q61L mutations mostly co-occurred with other alterations, including well known driver alterations, such as KRAS G12C, authors should better discuss this crucial aspect.
- Authors should discuss the potential role of HRAS as a therapeutic target considering also mutations affecting other codons, since data specific for Q61L are missing.
- Authors assess different times that only three patients with HRAS mutant NSCLC have been reported in literature, is this in agreement with TCGA data? If authors are referring only to Q61L mutation they should carefully specify.
Author Response
Please see the attachment.
Author Response File: Author Response.docx
Round 2
Reviewer 2 Report
I thank the authors for their effort in addressing my issues.
The paper has been improved, but further clarifications are needed:
- The variant allele frequency should be reported for all identified variants, not only for HRAS mutations.
- This sentence “To our knowledge, only three other cases of NSCLC patients with HRAS-mutant tumours have been reported in literature (Table 2). According to the TCGA database (pro-jects TCGA-LUAD and TCGA-LUSC), HRAS mutations were found in 3/550 (0.55%) adenocarcinomas and 8/480 (1.67%) squamous cell carcinomas (data available online: https://portal.gdc.cancer.gov/). One adenocarcinoma had HRAS p.Gln61Leu mutation. So far, all published cases were HRAS p.Gln61Leu mutations” is not clear and should be rephrased.
Do authors mean that only three cases of lung adenocarcinoma with HRAS mutations were described and all of them harboured Q61L mutations or that only three cases with Q61L HRAS mutations were described, but also other HRAS mutations were reported in NSCLC? Only one out of three HRAS mutated cases from TCGA had Q61L HRAS mutation and the other two cases harboured other alterations?
- In the conclusion authors assessed “Two patients received immunotherapy, and appeared to benefit from it.”, this sentence is not supported by reported data, moreover these patients had also other mutations.
Author Response
Dear Reviewer,
We would like to thank you for the additional comments provided, and to help us improve the manuscript. Please find enclosed the response to your comments. We addressed these comments and modified the manuscript accordingly. A point-by-point response is detailed below and the modified text is written in red into the manuscript.
Yours sincerely,
Dr. Elvire Pons-Tostivint
I thank the authors for their effort in addressing my issues.
The paper has been improved, but further clarifications are needed:
1. The variant allele frequency should be reported for all identified variants, not only for HRAS mutations.
Response 1: We agree with this comment. Variant allele frequency is now provided for all identified variants among our patients in text.
2. This sentence “To our knowledge, only three other cases of NSCLC patients with HRAS-mutant tumours have been reported in literature (Table 2). According to the TCGA database (pro-jects TCGA-LUAD and TCGA-LUSC), HRAS mutations were found in 3/550 (0.55%) adenocarcinomas and 8/480 (1.67%) squamous cell carcinomas (data available online: https://portal.gdc.cancer.gov/). One adenocarcinoma had HRAS p.Gln61Leu mutation. So far, all published cases were HRAS p.Gln61Leu mutations” is not clear and should be rephrased.
Do authors mean that only three cases of lung adenocarcinoma with HRAS mutations were described and all of them harboured Q61L mutations or that only three cases with Q61L HRAS mutations were described, but also other HRAS mutations were reported in NSCLC? Only one out of three HRAS mutated cases from TCGA had Q61L HRAS mutation and the other two cases harboured other alterations?
Response 2: We thank the reviewer to help us clarify this paragraph. According to our research, only three cases of lung adenocarcinoma with HRAS mutations were described, and all harbourded Q61L mutations. We didn’t find other cases of HRAS mutant cases with clinical features described in literature. In TCGA, we found 3 cases of HRAS mutations and only one of them harboured Q61L mutation, without clinical features described. To be more comprehensive, we rephrase the paragraph as following:
“To our knowledge, only three other individual clinical cases of NSCLC patients with HRAS-mutant tumours have been described in literature. All cases were p.Gln61Leu mutations (Table 2). According to the TCGA database (pro-jects TCGA-LUAD and TCGA-LUSC), HRAS mutations were found in 3/550 (0.55%) adenocarcinomas and 8/480 (1.67%) squamous cell carcinomas (data available online: https://portal.gdc.cancer.gov/). One adenocarcinoma had HRAS p.Gln61Leu mutation.”
3. In the conclusion authors assessed “Two patients received immunotherapy, and appeared to benefit from it.”, this sentence is not supported by reported data, moreover these patients had also other mutations.
Response 3: We thank the reviewer for this comment. Indeed, most of the patients in our study presented co-occuring mutations in MAPK pathway and TP53. We remove the sentence cited by the reviewer, and change the conclusion:
“Further studies are needed to better understand clinical course and prognosis associated with these mutations. However, preliminary data seems to show an association with tabagic status, aggressive presentation and co-occurring mutations in MAPK pathway and TP53.”
Round 3
Reviewer 2 Report
I thank the authors for their effort in addressing my issues.
