Seminar by members of the CCQM group of our department.

For the third talk, Mr. Zheyao Hu (PhD researcher at the UPC awarded by the China Scholarship Council program) will present the topic entitled: "Advances in strategies to directly and indirectly treat RAS-driven cancers: impact of KRAS-G12/NRAS-Q61 mutations and the case of SOS1-KRAS interactions”.

  • Seminar by members of the CCQM group of our department.
  • 2024-07-05T10:30:00+02:00
  • 2024-07-05T13:00:00+02:00
  • For the third talk, Mr. Zheyao Hu (PhD researcher at the UPC awarded by the China Scholarship Council program) will present the topic entitled: "Advances in strategies to directly and indirectly treat RAS-driven cancers: impact of KRAS-G12/NRAS-Q61 mutations and the case of SOS1-KRAS interactions”.
When

Jul 05, 2024 from 10:30 AM to 01:00 PM (Europe/Madrid / UTC200)

Where

B4-212 Campus Nord UPC

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I am pleased to announce a new seminar by members of our department's CCQM group.

For the third talk, Mr. Zheyao Hu (PhD researcher at the UPC with a scholarship from the China Scholarship Council program) will introduce us

the topic titled: "Advances in Strategies to Directly and Indirectly Treat RAS-Driven Cancers: Impact of Mutations"

KRAS-G12/NRAS-Q61 and the case of SOS1-KRAS interactions”.

Summary:

RAS (KRAS, NRAS and HRAS) are the most frequently mutated gene families in cancers. For more than three decades, few effective therapeutics have been developed to directly inhibit RAS-driven oncogenesis. To date, only two drugs (AMG510 sotorasib and MRTX849 adagrasib) related to the KRAS-G12C mutation have been approved. In contrast to direct targeting of RAS, indirect ways to treat RAS-driven cancers have also become a new hot topic, such as regulation of SOS1-RAS interactions and RAS effector proteins in the pure unmutated First, using atomically detailed microsecond-scale molecular dynamics simulations, we investigated KRAS-G12 mutations (associated with pancreatic, colon, and lung cancers) and NRAS-Q61 mutations (associated with melanoma). Two pharmacological pockets located in KRAS-G12D and one targetable pocket common to all NRAS-Q61 positively charged mutations (NRAS-Q61R and NRAS-Q61K) were identified. Subsequently, based on the drug design, we have created a protocol called "isomer source structure iteration method" (ISSI) for the in silico development of inhibitors and the prototypes have been developed of drugs DBD15-21-22 and HM-387, to directly treat KRAS-G12D and NRAS-Q61, respectively. In indirect treatments, we investigated the impact of the KRAS-G12D mutation on KRAS-SOS1 interactions. SOS1 acts by upregulating the KRAS GDP-GTP balance, promoting the sustained activation of KRAS mutations that ultimately leads to the development of cancers. For the non-mutated KRAS bound to GDP, four amino acids (Lys811, Glu812, Lys939 and Glu942) responsible for the catalytic function of SOS1 have been identified. With the appearance of the KRAS-G12D mutation, the mutated Asp12 residue interacts with the positively charged pocket (composed of Ser807, Trp809, Thr810 and Lys811) located in SOS1, significantly increasing the rate of GDP extraction.  Our investigations provide new insights into SOS1-KRAS interactions and facilitate the development of anti-cancer strategies based on blocking the previously described mechanisms.