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Page 8 of 11 Marchand-Adam et al. Rare Dis Orphan Drugs J 2023;2:3 https://dx.doi.org/10.20517/rdodj.2022.24

inhibitors or carbonic anhydrase inhibitors. Impressively, inhibition of mTOR by rapamycin also abrogated
acidification in a cell culture model by acting on cell metabolism rather than solely on the transporters
themselves. Thus, inhibition of extracellular acidification may be an alternative therapy for LAM by indirect
[60]
impairment of CatK activity .

As previously mentioned, inhibition of the mTOR pathway by rapamycin is currently the only reference
therapy for LAM. This beneficial effect may be related to the suppression of Warburg metabolism and
extracellular acidification. Accordingly, pharmacological inhibitors of carbonic anhydrases and sodium-
bicarbonate co-transporters have been successfully used in preclinical cancer models [65,66] and may have
synergistic benefits with mTOR inhibition in LAM to reduce detrimental proteases activity, including CatK.
Interestingly, markers for LAM cells, fibroblasts, lymphatics, and mast cells were examined by dual
immunohistochemistry, quantitated in LAM nodules, and compared with clinical features and prospective
lung function loss. Levels of CatK were negatively correlated with FEV1 and DLCO, while a higher
reactivity to the mTOR complex 1 activation marker was associated with a better lung function response to
rapamycin . Taken together, results suggested that an increase in CatK expression is associated with
[67]
severity of the disease and loss of lung function. At last, the higher prevalence of osteoporosis in LAM than
in the general population strengthens the interest in specifically targeting CatK . Interestingly, some recent
[68]
[69]
reports suggested that overexpression of CatK is associated with mTOR upregulation , while CatK could
promote tumor cell proliferation, invasion and migration, and its mechanism may be related to mTOR
signaling pathway . On the other hand, expression of cysteine cathepsins (including CatK and CatS) is
[70]
associated, via the inhibition of mTOR, with a decreased phosphorylation of TFEB (transcription factor EB),
a central regulator of autography/lysosomal biogenesis [34,71] . Therefore, although there is a scarcity of
experimental data, the possibility that rapamycin may have an impact on CatK expression cannot be ruled
out.

To summarize, combining the current treatment with rapamycin with the inhibition of collagenolytic CatK
by ectosteric inhibitors could be more effective than mTOR inhibition alone. Indeed, a cooperative curative
outcome in reducing lung destruction in LAM could be expected compared to a single therapeutic targeting.
In our opinion, such a dual approach is conceivable despite a lack of experimental evidence at this
hypothetical clinical stage.

DECLARATIONS
Acknowledgments
We gratefully acknowledge the patient association “French Lymphangioleiomyomatosis” (FLAM) for their
kind support. We thank The University Hospital Center of Tours (CHU Tours, Protocol Collaboration
Agreement: RIPH3 / LAM-CAK).

Authors’ contributions
Draft the paper: Lalmanach G, Lecaille F, Marchand-Adam S
Prepared the figures: Lecaille F, Lalmanach G
Wrote the paper: Lalmanach G
Revised the paper: Saidi A, Pronost M
All authors read and approved the final manuscript

Availability of data and materials
Not applicable.