Can­cer: New tar­get found for drug-re­sis­tant tu­mors

Tehran Times - - HEALTH -

Ra­pamycin and drugs that act like it have a lim­ited ef­fect against many can­cers be­cause their tu­mors are re­sis­tant to them. Now, the dis­cov­ery of a cell growth mech­a­nism could lead to new drugs that over­come this re­sis­tance in some can­cers.

The mech­a­nism in­volves a pre­vi­ously un­known pro­tein com­plex called mam­malian tar­get of ra­pamycin com­plex 3 (mTORC3).

Sci­en­tists at St. Jude Chil­dren’s Re­search Hos­pi­tal in Mem­phis, TN, came across it by chance when they were do­ing an ex­per­i­ment.

Their study is the sub­ject of a pa­per that now fea­tures in the jour­nal Sci­ence Ad­vances.

“This new com­plex,” ex­plains se­nior study au­thor Ger­ard C. Grosveld, who is the chair of the ge­net­ics de­part­ment at the hos­pi­tal, “has not been on any­body’s radar screen, even though mTOR com­plexes have been stud­ied for the last 25 years.”

He and his team de­scribe the find­ing as a “par­a­digm shift” in our un­der­stand­ing of an im­por­tant cell growth mech­a­nism and de­clare that it of­fers a “novel tar­get for an­ti­cancer drug de­vel­op­ment.”

Cell growth reg­u­la­tor

The en­zyme mam­malian (or mech­a­nis­tic) tar­get of ra­pamycin (mTOR) plays a key role in the con­trol of cru­cial cell pro­cesses; it reg­u­lates growth and keeps it in a state of equi­lib­rium.

Ab­nor­mal ac­ti­va­tion of mTOR ap­pears as a fac­tor in an “in­creas­ing num­ber” of dis­eases; as well as can­cer, th­ese in­clude neu­rode­gen­er­a­tion, type 2 di­a­betes, and obe­sity.

In can­cer, ab­nor­mal mTOR ac­ti­va­tion pro­motes tu­mor growth. Ra­pamycin, as well as drugs that act like it — known as ra­palogs — are de­signed to stop this by block­ing mTOR.

Most ra­palogs, how­ever, have lim­ited ef­fect in can­cer be­cause tu­mor cells are re­sis­tant to them.

Sci­en­tists had al­ready re­vealed that mTOR ex­erted its wide in­flu­ence from within two large pro­tein com­plexes:

mTORC1 and mTORC2.

Grosveld and his team, how­ever, re­cently came across ev­i­dence to sug­gest that there might be a third mTOR pro­tein com­plex, and that a tran­scrip­tion fac­tor pro­tein called

ETV7 as­sem­bled it.

The ex­per­i­ment that sug­gested this also re­vealed that over­ac­tive ETV7 was linked to over­ac­tive mTOR.

The re­searchers now plan to find drugs that block mTORC3 by tar­get­ing ETV7. They sug­gest that com­bin­ing such a drug with those that tar­get mTORC1 and mTORC2 could make many can­cers vul­ner­a­ble to ra­palogs that are oth­er­wise re­sis­tant to them.

ETV7 as­sem­bles mTORC3

By search­ing through sev­eral sources of ge­nomic can­cer data, the in­ves­ti­ga­tors re­vealed that ETV7 was ab­nor­mally over­ex­pressed in a large pro­por­tion of cases in sev­eral types of can­cer.

The team found ETV7 over­ex­pres­sion, for in­stance, in acute myeloid leukemia, acute lym­phoblas­tic leukemia, “pe­di­atric solid tu­mors,” a type of pe­di­atric brain tu­mor called medul­loblas­toma, and liver can­cer.

Fol­low­ing this, they car­ried out cell cul­ture tests and found that ETV7 caused mTOR to be­come over­ac­tive, and that this ac­cel­er­ated cell growth.

The sci­en­tists were mys­ti­fied, how­ever, by the fact that ETV7 did not seem to be do­ing this as part of the pro­tein com­plexes mTORC1 or mTORC2.

Even­tu­ally, af­ter an­other set of ex­per­i­ments, they found that ETV7 was or­ches­trat­ing the as­sem­bly of a dis­tinct mTOR pro­tein com­plex to which they as­signed the name mTORC3.

Re­mov­ing ra­pamycin re­sis­tance

Th­ese ex­per­i­ments con­firmed that nei­ther mTORC1 nor mTORC2 con­tained ETV7 and showed that mTORC3 was com­pletely re­sis­tant to ra­pamycin.

The sci­en­tists then demon­strated that delet­ing ETV7 in tu­mor cells that were re­sis­tant to ra­pamycin made them vul­ner­a­ble to the drug.

A fi­nal set of tests in mice ge­net­i­cally en­gi­neered to de­velop tu­mors in their mus­cles showed that mTORC3 pro­duc­tion made the tu­mors more ag­gres­sive and sped up their growth.

The re­searchers now plan to find drugs that block mTORC3 by tar­get­ing ETV7. They sug­gest that com­bin­ing such a drug with those that tar­get mTORC1 and mTORC2 could make many can­cers vul­ner­a­ble to ra­palogs that are oth­er­wise re­sis­tant to them.

“We have de­vel­oped solid data for the ex­is­tence of mTORC3, and now, we are seek­ing to iso­late and iden­tify the com­po­nents of the com­plex,” Ger­ard C. Grosveld said.

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