Here we go.....this is not an obscure link that I just handpicked.
There is plenty of other discussion, that alpelisib is not working as well as it might (resistance to agent, and subsequent PTEN loss) because it is a single isoform alpha activation.
Not at all hard to understand.....but what is hard to reason is the SP.
A potential SP now that is many many multiples below a net present worth value - after all the usual and proven calculations for time delays to profit and risk of non approval. So hey - what does that mean a 40% chance that this drug will be the sought after general purpose PI3K inhibitor - if so in 3 to 5 years time, it would be generate sales of $20 billion PA....or profits of $10b PA.
So the overriding point - completely nothing to do with what one maverick has to say, who does not believe what he types anyway....... I think the management needs to do more to get the message out there, starting yesterday.
-----------------------------------------------
Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitorNov. 18, 2019
SCIENTIFICNatureVOLUME 518, pages240–244(2015)
Revisiting old data following the recent approval of alpelisib in PIK3CA-mutant breast cancer- a 2015 study identified PTEN loss with consequent PI3K-beta activation as a common mechanism of resistance to this agent.
ABSTRACTBroad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating
PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα
mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of
PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different
PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of
PTEN was found in one of these patients, whereas in two others
PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of
PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in
PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110β blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different
PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.
