UCL Cancer Institute Special Seminar

Dr Pau Castel, Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, presents: Mechanisms of resistance to PI3Kα inhibitors, Monday 25th July, 12pm

The exponential development in high-throughput sequencing techniques has revealed the most frequently mutated oncogenes in human cancers. Among these, PIK3CA mutations appear to be prevalent in several tumors such as breast, head and neck, and cervical cancers. Current therapeutic efforts are aimed to inhibit the PI3Kα oncoprotein, which is encoded by PIK3CA. Despite the encouraging results obtained from early clinical trials, it is becoming evident that resistance to PI3Kα inhibitors commonly emerges, therefore combination with other targeted therapies and patient stratification will be necessary. We will discuss the preclinical results obtained in our laboratory regarding mechanisms of resistance to these inhibitors and propose therapeutic combinations that are likely to increase the clinical benefit. 

Host: Professor Bart Vanhaesebroeck

References

1. Castel P, Ellis H, Bago R, Toska E, Kannan S, Carmona FJ, Razavi P, Verma CS, Dickler M, Chandarlapaty S, Brogi E, Alessi DR, Baselga J, Scaltriti M. PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kα inhibition. 2016; Cancer Cell, In press.
2. Castel P, Carmona FJ, Grego-Bessa J, Berger MF, Viale A, Anderson KV, Bague S, Scaltriti M, Antonescu CR, Baselga E, Baselga J. Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci Transl Med. 2016 Mar 30;8(332):332ra42.
3. Juric D*, Castel P*, Griffith M, Griffith OL, Won HH, Ellis H, Ebbesen SH, Ainscough BJ, Ramu A, Iyer G, Shah RH, Huynh T, Mino-Kenudson M, Sgroi D, Isakoff S, Thabet A, Elamine L, Solit DB, Lowe SW, Quadt C, Peters M, Derti A, Schegel R, Huang A, Mardis ER, Berger MF, Baselga J, Scaltriti M. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature. 2015 Feb 12;518(7538):240-4.  * joint first author
4. Tao JJ*, Castel P*, Radosevic-Robin N, Elkabets M, Auricchio N, Aceto N, Weitsman G, Barber P, Vojnovic B, Ellis H, Morse N, Viola-Villegas NT, Bosch A, Juric D, Hazra S, Singh S, Kim P, Bergamaschi A, Maheswaran S, Ng T, Penault-Llorca F, Lewis JS, Carey LA, Perou CM, Baselga J, Scaltriti M. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal. 2014 Mar 25;7(318):ra29. * joint first author
5. Castel P, Toska E, Zumsteg ZS, Carmona FJ, Elkabets M, Bosch A, Scaltriti M. Rationale-based therapeutic combinations with PI3K inhibitors in cancer. Molecular and Cellular Oncology, 2014, Sep; doi: 10.4161/23723548.2014.963447. Review.

Location

UCL Cancer Institute
4th Floor meeting room
Paul O'Gorman Building
72 Huntley Street
London, WC1E 6DD